一种治疗代谢疾病的多结构域活性蛋白的制作方法

本发明属于生物药物领域，具体涉及一种治疗代谢疾病的多结构域活性蛋白。
背景技术：
：糖尿病按病理特征可分为一型糖尿病和二型糖尿病两种。一型糖尿病主要表现为胰岛素分泌不足，需要每天注射胰岛素；而二型糖尿病则是由于人体无法有效利用胰岛素造成。其中二型糖尿病患者占绝大多数。据估计大约80-90％二型糖尿病患者明显肥胖(centerfordiseasecontrolandprevention(cdc)nationaldiabetesfactsheet,2014)。用于治疗二型糖尿病的常规化药如磺酰脲类，噻唑烷二酮类等降糖效果明显，但主要缺点是会导致体重增加(kahnse,haffnersm,heisema,hermanwh,holmanrr,jonesnp,etal.glycemicdurabilityofrosiglitazone,metformin,orglyburidemonotherapy.nengljmed2006；355(23):2427-43.)。而用于二型糖尿病的蛋白类药物主要是glp-1r(glp-1受体)激动剂，如杜拉鲁肽(dulaglutide，商品名：)、阿必鲁肽(albiglutide，商品名)、利拉鲁肽(liraglutide，商品名及分别用于治疗肥胖和糖尿病)、艾塞那肽(exenatide，商品名)、利西拉肽(lixisenatide，商品名)及索马鲁肽(semaglutide)等。glp-1r激动剂具有显著的降血糖效应，而且与胰岛素不同的是，glp-1r激动剂的降糖作用是严格地血糖依赖性的，不容易造成低血糖，还有降体重的效果。例如，杜拉鲁肽的减重大约为2.9公斤，而被批准用于减肥的liraglutide(一天一次，剂量3mg)减重约8公斤。这些药物的减重主要是通过食欲控制，而且大部分都不超过平均体重的10％。减肥手术(bariatricsurgery)虽然可以显著改善肥胖症和治疗糖尿病，然而其应用并不广泛，因为大部分的患者出于手术风险及长期后遗症的考虑，并不愿意接受这种手术(obesityanddiabetes，newsurgicalandnonsurgicalapproaches，springer出版社，2015)。据报道，经外科减肥手术的患者肠降血糖素(incretin)分泌会激增(obesityanddiabetes，newsurgicalandnonsurgicalapproaches，springer出版社，2015)。因此，目前新一代的糖尿病药物主要集中于双效或多效肠降血糖素(incretin)受体激动剂的研究，如glp-1r/gipr和glp-1r/gcgr双效激动剂，甚至glp-1r/gipr/gcgr三效激动剂。其中，胰高血糖素(glucagon)和glp-1(glucagon-likepeptide-1)的受体在结构上相关，但是这两种激素在控制葡萄糖中表现出截然相反的作用。临床上，glp-1及其类似物主要用于糖尿病人的血糖控制，而胰高血糖素(glucagon)则用于急性低血糖症。近年来，越来越多的研究证明，胰高血糖素(glucagon)尽管存在升血糖的风险，但是却能有效减少体重；更重要的是，glp-1与glucagon似乎有正向的附加或协同生理作用，例如glucagon受体(gcgr)与glp-1受体(glp-1r)双激动剂比glp-1r单激动剂能更有效地减重。虽然gcgr激动可能会导致血糖水平增加，但是这个风险可以通过glp-1r激动而适当地抵消。目前glp-1r和gcgr的双效激动剂普遍都是基于胃泌酸调节素(oxyntomodulin)或glucagon，并且为了改善其短效及酶解的缺陷而进行改造(oxyntomodulin类似物或glucagon类似物)。这些类似物大都将第二位的丝氨酸(ser)突变成非天然氨基酸aib来抵抗dpp-iv的酶解。这是因为天然的glucagon与胃泌酸调节素都与天然glp-1类似，极易遭受血清中dpp-iv蛋白酶的水解而导致失活(victora.gault等，anovelglp-1/glucagonhybridpeptidewithtriple-actingagonistactivityatgip,glp-1andglucagonreceptorsandtherapeuticpotentialinhigh-fatfedmice，jbiolchem.,288(49):35581-91.2013；bhatvk等，adpp-iv-resistanttriple-actingagonistofgip,glp-1andglucagonreceptorswithpotentglucose-loweringandinsulinotropicactionsinhigh-fat-fedmice，diabetologia，56(6):1417-24.2013；johna.pospisilik等；metabolismofglucagonbydipeptidylpeptidaseiv(cd26)，regulatorypeptides96:133–141,2001；hinkesa等，dipeptidylpeptidaseiv(dpiv/cd26)degradationofglucagon.characterizationofglucagondegradationproductsanddpiv-resistantanalogs，jbiolchem275:3827–3834,2000；alessiasantoprete等，dpp-iv-resistant,long-actingoxyntomodulinderivatives,j.pept.sci.,17:270–280,2011)。fgf21属于在发育以及成体组织中广泛表达的在多种生理功能中起重要作用的多肽家族成员。fgf21主要表达于胰腺β细胞、肝脏、wat、骨骼肌，近来发现其在胸腺、血管内皮、肾脏、睾丸组织中也有较低表达，有明显的组织特异性，和fgf15/19、fgf23同属于fgf家族“内分泌”激素。fgf21作为一种重要的代谢调节剂已经在ii型糖尿病临床前模型(t2dm)实验中被证明能够改善多种代谢异常。fgf21作为糖尿病患者的治疗药物在提高胰岛素敏感性，改善血糖控制，减轻体重，降低低密度脂蛋白胆固醇(ldl-c)和甘油三酯，同时增加高密度脂蛋白胆固醇水平(hdl-c)这些方面有潜在作用。在糖尿病鼠和猴子中，人fgf21能够降低空腹血清葡萄糖浓度，减少空腹血清甘油三酯，胰岛素和胰高血糖素的浓度。此外，在饮食诱导肥胖的啮齿动物模型中，fgf21给药导致剂量依赖的总体重减轻。因此，fgf21具有治疗糖尿病，肥胖，血脂异常和代谢综合征等疾病的潜力。但是，fgf21具有非常短的血清半衰期：小鼠体内30分钟，猴子2小时。因此，为了维持体内生物活性需要每日注射或连续输注相应fgf21蛋白质。在人体研究中，在肥胖、血脂异常、tdm2及其他与胰岛素抵抗相关疾病的患者体内，循环fgf21水平往往升高，有研究表明fgf21浓度增加与cvd风险增加有关联，还会导致骨质疏松，影响生殖(促进新陈代谢进而导致能量不足)等(weiw,dutchakpa,wangx,dingx,wangx,bookoutal,etal.fibroblastgrowthfactor21promotesbonelossbypotentiatingtheeffectsofperoxisomeproliferator-activatedreceptorgamma.procnatlacadsciusa.2012；109(8):3143–8；fibroblastgrowthfactor21hasnodirectroleinregulatingfertilityinfemalemice，molmetab，5(8):690-8，2016)。fgf家族序列的同源性以及fgfr1受体的广泛分布，也对临床大剂量使用fgf21所带来的潜在安全性问题带来关注(kharitonenkova&dimarchir:fibroblastgrowthfactor21nightwatch:advancesanduncertaintiesinthefield.jinternmed.2017mar；281(3):233-246.)。gcgr/glp-1r双效激动剂及fgf21类似物都分别用于治疗糖尿病及减重，另外还有将glp-1类似物与fgf21通过fc融合制备成双效活性蛋白的报道(yh25723,anovellong-actingglp-1/fgf21dualagonistprovidesmorepotentandsustainedglycemiccontrolandgreaterweightlosscomparedwithsingleagonistsinanimalmodels，theamericandiabetesassociation，2016)。如上所述，目前基于glucagon或胃泌酸调节素改造而成的双效甚至三效多肽普遍需要将部分氨基酸取代非天然氨基酸来提高稳定性和活性，甚至还需要通过脂肪酸或peg修饰，技术上极难与fgf21类似物融合表达制备成单一分子。目前也并无关于双效或者多效激动剂类多肽与fgf21类似物组合用药的报道。技术实现要素：为了克服现有技术中所存在的问题，本发明的目的在于提供一种治疗代谢及相关疾病的多结构域活性蛋白及其制备与应用。本发明的多重活性蛋白具有显著的减重效果，临床可以用于治疗糖尿病、减肥、非酒精性脂肪肝、高血脂等相关疾病。为了实现上述目的以及其他相关目的，本发明采用如下技术方案：本发明的第一方面，提供一种多结构域活性蛋白，其结构中包括如式i所示的结构，如式i所示结构为：a-la-f-lb-b，其中，a为gcgr/glp-1r双效激动活性肽，f为长效蛋白单元，b为天然fgf21或fgf21类似物，la不存在或为连接链，lb不存在或为连接链。所述多结构域活性蛋白具有至少glp-1、gcg和fgf21三效活性。进一步地，式i中，所述a包括如式ii所示的结构，如式ii所示结构为：hsqgtftsd-x10-s-x12-x13-x14-x15-x16-x17-x18-x19-x20-x21-f-x23-x24-wl-x27-x28-x29-x30-xz。其中，所述x10选自v、l或y之任一；所述x12选自s、e或k之任一；所述x13选自y或q之任一；所述x14选自l或m之任一；所述x15选自d或e之任一；所述x16选自s、e或g之任一；所述x17选自r、e或q之任一；所述x18选自r、e或a之任一；所述x19选自a或v之任一；所述x20选自q、r或k之任一；所述x21选自d、l或e之任一；所述x23选自v或i之任一；所述x24选自q、a或e之任一；所述x27选自m、k或v之任一；所述x28选自n或k之任一；所述x29选自g或t之任一；所述x30为g或缺失；所述xz不存在或选自gpssgappps(seqidno.3)、pssgappps(seqidno.4)、ssgappps(seqidno.5)、gpssgapps(seqidno.6)、pssgapps(seqidno.7)或krnrnnia(seqidno.8)之任一。进一步地，所述a的氨基酸序列如seqidno.44～92之任一所示。式i中，所述的b为天然fgf21(seqidno.136)或者fgf21类似物。所述b包括如下结构：hpipdsspllqfggqvrqx19ylytddaqqtex31hleix36edgtvgx43ax45dqspesllqlx56alkpgviqilgvktsrflcqrpdgalygslhfdpeacsfrex98lledgynvyqseahglplhx118pgnx122sphrdpaprgpx134rflplpglppalpeppgilapqppdvgssdplx167mvx170x171sqx174rspsx179x180x181，其中，n端hpipdss可缺失或部分缺失；x19选自r、y、v、e或c；x31选自a或c；x36选自r或k；x43选自g或c；x45选自a、k、e或v；x56选自k、r、v或i；x98选自l、r或d；x118选自l或c；x122选自k或r；x134选自a或c；x167选自s、a或r；x170选自g或e；x171选自p或g；x174选自g、a或l；x179选自y、a或f；x180选自a或e；x181选自s、k或缺失。所述的fgf21类似物为与天然fgf21(seqidno.136)具有相同或相似生物学功能、且与天然fgf21(seqidno.136)同源性为80％以上的活性蛋白。优选地，所述fgf21类似物与天然fgf21(seqidno.136)同源性为85％以上；更优选地，所述fgf21类似物与天然fgf21(seqidno.136)同源性为90％以上；更优选地，所述fgf21类似物与天然fgf21(seqidno.136)同源性为95％以上。示例性地，所述的fgf21类似物可选自如us20140213512、us8188040、us9493530、wo2016114633、us20150291677、us9422353、us8541369、us7622445、us7576190、us20070142278、us9006400或us20130252884等专利或专利申请中所描述的fgf21类似物或突变体。优选地，所述fgf21类似物如seqidno.137-148所示。进一步地，所述f为源自哺乳动物免疫球蛋白的fc部分。所述免疫球蛋白是含有二硫键的多肽链分子，一般具有两条轻链和两条重链。此处用到的免疫球蛋白的fc部分具有免疫学领域术语的常用含义。具体的，该术语是指通过从抗体中去除两个抗原结合区(fab片段)而得到的抗体片段。fc部分可以包括铰链区并且延伸通过ch2和ch3结构域到达抗体c末端。fc部分可以进一步包括一个或多个糖基化位点。人体有5种具有不同效应特征和药代动力学特性的人免疫球蛋白：igg、iga、igm、igd和ige。igg是血清中含量最高的免疫球蛋白。igg在所有的免疫球蛋白中也是血清半衰期最长的(约23天)。进一步地，f可选自免疫球蛋白的完整fc部分、免疫球蛋白的fc部分的片段或免疫球蛋白的fc部分的突变体。用于本发明的免疫球蛋白fc部分来源于哺乳动物igg1、igg2或igg4的fc区或其突变体；优选的，可以是来源自人的igg1、igg2或igg4的fc区或其突变体；更优选的，可以来源自人igg1或igg4的fc区或其突变体。在一个优选的实施方案中，fc结构域的第297位被甘氨酸或丙氨酸替换。上述内容是依照kabat的eu索引编号(kabat,e.a.等，sequencesofproteinsofimmunologicalinterest，第五版，publichealthservice,nationalinstitutesofhealth,bethesda,md(1991))。在一个优选的实施方案中，fc结构域来自人igg4，并如seqidno.16所示。在一个优选的实施方案中，所述fc结构域来自人igg1，如seqidno.12所示。所述fc链末端的k可去除，便于提高表达产物的均一性。在一些实施方式中，所述f的氨基酸序列可以如seqidno.9～18之任一所示。本发明上述多结构域活性蛋白中，所述gcgr/glp-1r双效激动活性肽a通过长效蛋白单元f与天然fgf21或fgf21类似物b融合，形成具有至少glp-1、gcg和fgf21三效活性的重组融合蛋白。a与f之间可以通过连接链连接，如la，也可以不加入连接链而直接融合。f与b之间可以通过连接链连接，如lb，也可以不加入连接链而直接融合。当la和lb为连接链时，所述连接链为一段合适长度的由甘氨酸(g)、丝氨酸(s)和/或丙氨酸(a)构成的柔性多肽，从而使相邻的蛋白质结构域可相对于彼此自由移动。当有必要保证所述两个相邻结构域空间上彼此互不干扰时，可以使用较长的连接链。本发明优选的连接链包括含富含g、s和/或a的单元，示例性的如(gs)n，(ggs)n，(ggsg)n，(gggs)na，(ggggs)na、(gggga)na、等，n为1-10的整数，在一个优选的实施方案中，所述的连接链的氨基酸长度为5-26。示例性的连接链各自独立的选自表2。进一步地，所述连接链的氨基酸序列可如seqidno.19～41之任一所示。进一步地，所述多结构域活性蛋白的氨基酸序列如seqidno.150～208之任一所示。本发明提供的多结构域活性蛋白是一种fc融合蛋白，保留了fc的常规特性，如与fcrn结合而延长体内半衰期，以及在分离纯化过程中通过与proteina或g类填料高亲和力和高特异性地结合而达到高效纯化目的的性质。另外，这些多结构域活性蛋白除了能有效地抵抗血清内的蛋白酶对蛋白内部的降解外，还能有效地防止n端的降解。对于incretin类多肽如glucagon或glp-1而言，n端的完整性是决定其生物学活性的关键。天然glucagon和glp-1在体内的半衰期短，除了分子量小这个原因外，更重要的是由于受体内的dpp-iv酶水解及多肽内部的水解。在本发明的一个实施例中，天然glucagon与fc融合后，依然会被dpp-iv快速地降解而失活；而对应的glucagon类似物却能明显地抵抗dpp-iv的攻击。本发明的第二方面，提供一种分离的多核苷酸，所述分离的多核苷酸编码前述多结构域活性蛋白。本发明的第三方面，提供一种重组表达载体，包含前述分离的多核苷酸。本发明的第四方面，提供一种宿主细胞，所述细胞含有前述重组表达载体或基因组中整合有外源的前述分离的多核苷酸。本发明的第五方面，提供前述多结构域活性蛋白的制备方法，包括在合适的条件下培养前述宿主细胞，使之表达所述多结构域活性蛋白，而后分离及纯化获得所述多结构域活性蛋白。本发明的第六方面，提供前述多结构域活性蛋白在制备治疗糖尿病代谢相关疾病的药物中的用途。本发明提供的多结构域活性蛋白可以用于治疗代谢综合征。代谢综合征的特征通常在于簇集至少三种以上的以下风险因素：(1)腹部肥胖(腹部内或周围脂肪组织过多)，(2)致动脉粥样硬化血脂异常，血脂失调，包括高甘油三酯、低hdl胆固醇及高ldl胆固醇，其增强动脉壁中斑块的积累，(3)血压升高，(4)胰岛素抗性或葡萄糖耐受不良，(5)血栓样状态，例如血液中高纤维蛋白或纤溶酶原活化因子抑制剂-1，以及(6)促发炎状态，例如血液中c反应性蛋白升高。其他风险因素可包括老化、激素失衡及遗传因素。此外，本发明的多结构域活性蛋白还可用于治疗肥胖症。在一些方面中，本发明的多多结构域活性蛋白通过降低食欲、减少食物摄取、降低患者体内脂肪水平、提高能量消耗等机制来治疗肥胖症。本发明的第七方面，提供一种治疗代谢相关疾病的方法，包括向对象施用前述多结构域活性蛋白。本发明进一步提供一种促进体重减少或者防止体重增加的方法，包括在对象中施用所述的多结构域活性蛋白。本发明的第八方面，提供一种组合物，含有前述多结构域活性蛋白或前述宿主细胞的培养物，以及药学上可接受的载体。本发明的第九方面，提供前述多结构域活性蛋白在制备融合蛋白中的用途。本发明的第十方面，提供一种融合蛋白，其结构中含有前述多结构域活性蛋白。本发明的第十一方面，提供另外一种治疗代谢及相关疾病的组合物，包括gcgr/glp-1r双效激动活性蛋白和长效fgf21类似物。所述gcgr/glp-1r双效激动活性蛋白的结构中包括：a-la-f，所述a的结构中包括如式ii所示结构，如式ii所示结构为：hsqgtftsd-x10-s-x12-x13-x14-x15-x16-x17-x18-x19-x20-x21-f-x23-x24-wl-x27-x28-x29-x30-xz。其中，所述x10选自v、l或y之任一；所述x12选自s、e或k之任一；所述x13选自y或q之任一；所述x14选自l或m之任一；所述x15选自d或e之任一；所述x16选自s、e或g之任一；所述x17选自r、e或q之任一；所述x18选自r、e或a之任一；所述x19选自a或v之任一；所述x20选自q、r或k之任一；所述x21选自d、l或e之任一；所述x23选自v或i之任一；所述x24选自q、a或e之任一；所述x27选自m、k或v之任一；所述x28选自n或k之任一；所述x29选自g或t之任一；所述x30为g或缺失；所述xz不存在或选自gpssgappps(seqidno.3)、pssgappps(seqidno.4)、ssgappps(seqidno.5)、gpssgapps(seqidno.6)、pssgapps(seqidno.7)或krnrnnia(seqidno.8)之任一。所述f为长效蛋白单元，f可选自免疫球蛋白的完整fc部分、免疫球蛋白的fc部分的片段或免疫球蛋白的fc部分的突变体。进一步地，所述f的氨基酸序列如seqidno.9-18所示。la不存在或为连接链，当为连接链时，所述连接链为一段合适长度的由甘氨酸(g)、丝氨酸(s)和/或丙氨酸(a)构成的柔性多肽，从而使相邻的蛋白质结构域可相对于彼此自由移动。当有必要保证所述两个相邻结构域空间上彼此互不干扰时，可以使用较长的连接链。所述连接链示例性的如(gs)n，(ggs)n，(ggsg)n，(gggs)na，(ggggs)na、(gggga)na等，n为1-10的整数。示例性的连接链可各自独立的选自表2。进一步地，所述gcgr/glp-1r双效激动活性蛋白的氨基酸序列如seqidno.96、seqidno.98、seqidno.100、seqidno.102、seqidno.104、seqidno.106、seqidno.108、seqidno.110、seqidno.112、seqidno.114-133之任一所示。所述长效fgf21类似物的结构中包括：f-lb-b，所述b的结构中包括：hpipdsspllqfggqvrqx19ylytddaqqtex31hleix36edgtvgx43ax45dqspesllqlx56alkpgviqilgvktsrflcqrpdgalygslhfdpeacsfrex98lledgynvyqseahglplhx118pgnx122sphrdpaprgpx134rflplpglppalpeppgilapqppdvgssdplx167mvx170x171sqx174rspsx179x180x181，其中，n端hpipdss可缺失或部分缺失；x19选自r、y、v、e或c；x31选自a或c；x36选自r或k；x43选自g或c；x45选自a、k、e或v；x56选自k、r、v或i；x98选自l、r或d；x118选自l或c；x122选自k或r；x134选自a或c；x167选自s、a或r；x170选自g或e；x171选自p或g；x174选自g、a或l；x179选自y、a或f；x180选自a或e；x181选自s、k或缺失。所述的fgf21类似物为与天然fgf21(seqidno.136)具有相同或相似生物学功能、且与天然fgf21(seqidno.136)同源性为80％以上的活性蛋白。优选地，所述fgf21类似物与天然fgf21(seqidno.136)同源性为85％以上；更优选地，所述fgf21类似物与天然fgf21(seqidno.136)同源性为90％以上；更优选地，所述fgf21类似物与天然fgf21(seqidno.136)同源性为95％以上。示例性地，所述的fgf21类似物可选自如us20140213512、us8188040、us9493530、wo2016114633、us20150291677、us9422353、us8541369、us7622445、us7576190、us20070142278、us9006400或us20130252884等专利或专利申请中所描述的fgf21类似物或突变体。所述fgf21类似物如seqidno.137-148所示。所述f可选自免疫球蛋白的完整fc部分、免疫球蛋白的fc部分的片段或免疫球蛋白的fc部分的突变体。所述f的氨基酸序列可以如seqidno.9～18之任一所示。lb不存在或为连接链，当lb为连接链时，所述连接链包括含富含g、s和/或a的单元，示例性的如(gs)n，(ggs)n，(ggsg)n，(gggs)na，(ggggs)na、(gggga)na、等，n为1-10的整数，在一个优选的实施方案中，所述的连接链的氨基酸长度为5-26。示例性的连接链各自独立的选自表2。进一步地，所述连接链的氨基酸序列可如seqidno.19～41之任一所示。进一步地，所述长效fgf21类似物的氨基酸序列如seqidno:210-221之任一所示。本发明的第十二方面，提供前述组合物在制备治疗代谢相关疾病药物中的用途。本发明的第十三方面，提供另外一种治疗代谢相关疾病的方法，包括向对象施用前述包括gcgr/glp-1r双效激动活性蛋白和长效fgf21类似物的组合物。本发明进一步提供一种促进体重减少或者防止体重增加的方法，包括在对象中施用前述包括gcgr/glp-1r双效激动活性蛋白和长效fgf21类似物的组合物。众所周知，肠降血糖素(incretin)类激素蛋白如glp-1类似物、exendin-4等会让患者产生恶心、呕吐等副作用，而且是剂量相关的。因此在能维持理想的血糖水平的情况下，尽量减少给药剂量理论上会缓解患者的不适副作用。另外，fgf21对于骨质疏松及生殖影响方面的报道也时有报道(fibroblastgrowthfactor-21concentrationinserumandsynovialfluidisassociatedwithradiographicbonelossofkneeosteoarthritis.scandjclinlabinvest.2015apr；75(2):121-5；fibroblastgrowthfactor21hasnodirectroleinregulatingfertilityinfemalemice.molmetab.5(8):690-8，2016)。理论上，药物副作用产生的风险与给药剂量成正比，在糖尿病药物领域，对药物的安全性极高。发明人发现gcg/glp-1/fgf21三效活性蛋白以及上述组合物在很低剂量下就有很好的控制血糖和体重的效果，并且对胃肠道影响小，大大地减少了fgf21的剂量，因而显著降低起潜在副作用风险。与现有技术相比，本发明具有如下有益效果：(1)本发明的多结构域活性蛋白半衰期长、支持一周一次的给药频率；(2)本发明的多结构域活性蛋白的glp-1r激动活性最高提高到了200倍以上；(3)本发明的多结构域活性蛋白体内外稳定性好，且免疫原性低；(4)由于不需要引入非天然氨基酸，无需涉及化学合成及交联步骤，因此可通过重组方法制备，极大地简化了制备工序。附图说明图1为纯化获得的部分三效活性蛋白还原电泳图(10％sds-page)，泳道1-13分别为c002l13f4l10w、c240l12f8l12m1、c495l13f8l10m1、c266l13f7l13m4、c462l9f2l9m10、c611l11f4l11m11、c563l14f8l9m3、c382l13f8l10m2、c623l9f3l10m1、c731l5f2l9m9、c353l13f3l10m4、c227l12f5l14m4、c137l10f8l9m5；m为蛋白标准品：97.2、66.4、44.3、29、20.1、14.3kd。图2a：血清稳定性随时间变化的结果图。图2b：血清稳定性随时间变化的结果图。图2c：血清稳定性随时间变化的结果图。图3：实施例8中的活性蛋白在正常icr小鼠体内的降糖效果图。图4：实施例9中的活性蛋白对dio小鼠体重的影响作用。图5：实施例9中的活性蛋白对dio小鼠食欲的影响作用；以pbs组dio鼠的摄食量为100％，纵坐标为其他组的摄食量与之相比的百分比。图6：实施例10中的活性蛋白对dio小鼠体重的影响作用。图7：实施例10中的活性蛋白对dio小鼠食欲的影响作用；以pbs组dio鼠的摄食量为100％，纵坐标为其他组的摄食量与之相比的百分比。具体实施方式术语解释：术语“糖尿病”包括一型糖尿病、二型糖尿病、妊娠糖尿病以及引起高血糖症的其他症状。该术语用于代谢紊乱，其中胰腺产生不了足够的胰岛素，或身体的细胞未能适当响应胰岛素，因此组织细胞吸收葡萄糖效率下降导致葡萄糖在血液中积累。一型糖尿病也称为胰岛素依赖性糖尿病和幼年发病型糖尿病，通过β细胞破坏引起，通常导致绝对胰岛素缺乏。二型糖尿病也称为非胰岛素依赖性糖尿病和成年发病型糖尿病，普遍与胰岛素抗性相关。术语“肥胖”意指脂肪组织的过量，当能量摄取超过能量消耗时，过量卡路里贮存于脂肪中，则导致肥胖。在本文中体重指数(bmi＝体重(千克)除以身高(米)的平方)超过25的个体视为肥胖。肠降血糖素(incretin)：肠降血糖素是通过增强葡萄糖刺激的胰岛素分泌(亦称为葡萄糖依赖的胰岛素分泌，gsis)来调控血糖的胃肠激素(drucker.dj,nauck,ma,lancet368:1696-705,2006)。肠降血糖素还可通过延缓胃排空的方式减慢营养吸收的速度并直接地减少食物吸收。同时，肠降血糖素还抑制肠道α细胞分泌胰高血糖素(glucagon)。迄今为止有两种已知的肠降血糖素：胰高血糖素样肽-1(glp-1)和葡萄糖依赖性促胰岛素多肽(gip)。前胰高血糖素原(preproglucagon)：是158个氨基酸组成的前体多肽，其在组织中被差异性加工而形成多种结构上相关的胰高血糖素原衍生肽，包括胰高血糖素(glucagon)、胰高血糖素样肽-1(glp-1)、胰高血糖素样肽-2(glp-2)和胃泌酸调节素(oxyntomodulin，oxm)。gip：是由133个氨基酸的前体(pre-pro-gip)通过蛋白水解加工得到的42个氨基酸的肽，这些分子参与多种生物功能，包括葡萄糖体内平衡、胰岛素分泌、胃排空和肠生长以及食物摄取调节。胰高血糖素样肽(glp-1)：序列如seqidno：1所示；是从肠l-细胞分泌的30或31个氨基酸的多肽肠促胰岛素激素，有glp-1(7-36)和glp-1(7-37)两种活性形式。glp-1在进餐后释放到循环中，并通过激活glp-1受体发挥生物活性。glp-1具有许多生物学作用，包括葡萄糖依赖性的促胰岛素分泌，抑制胰高血糖素生成，延缓胃排空和抑制食欲(tharakang,tant,blooms.emergingtherapiesinthetreatmentof‘diabesity’:beyondglp-1.trendspharmacolsci2011；32(1):8-15.)等。天然glp-1由于能够被二肽基肽酶-4(dpp-4)，中性肽链内切酶(nep)，血浆激肽释放酶或纤溶酶等快速降解因而限制了其治疗潜力。由于天然glp-1在体内仅有大约2分钟的超短半衰期，因此，出现了通过利用化学修饰和/或制剂形式来改善功效以治疗糖尿病和肥胖症的方法(lorenzm,eversa,wagnerm.recentprogressandfutureoptionsinthedevelopmentofglp-1receptoragonistsforthetreatmentofdiabesity.bioorgmedchemlett2013；23(14):4011-8；tomlinsonb,hum,zhangy,chanp,liuzm.anoverviewofnewglp-1receptoragonistsfortype2diabetes.expertopininvestigdrugs2016；25(2):145-58)。胃泌酸调节素(oxyntomodulin)是37个氨基酸的小肽，序列如seqidno：2所示；其包含胰高血糖素glucagon(seqidno：42)完整的29个氨基酸序列。胃泌酸调节素是glp-1r和gcgr的双重激动剂，在进餐后通过肠l-细胞与glp-1一起分泌。与胰高血糖素glucagon类似，胃泌酸调节素在人和啮齿动物中产生显著的体重减轻。胃泌酸调节素的减肥活性已在肥胖小鼠中与等摩尔剂量的选择性glp-1激动剂进行比较。已经发现，与选择性的glp-1r激动剂相比，胃泌酸调节素具有抗高血糖作用，能够显著的减轻体重和具有降脂活性(theglucagonreceptorisinvolvedinmediatingthebodyweight-loweringeffectsofoxyntomodulin，kosinskijr等，obesity(silverspring)，20):1566-71，2012)。在超重和肥胖患者中，皮下施用天然胃泌酸调节素在四周内减少体重1.7公斤。胃泌酸调节素也被证明可以减少人类的食物摄取和增加能量消耗(subcutaneousoxyntomodulinreducesbodyweightinoverweightandobesesubjects:adouble-blind,randomized,controlledtrial，wynnek等，diabetes，54:2390-5，2005；oxyntomodulinincreasesenergyexpenditureinadditiontodecreasingenergyintakeinoverweightandobesehumans:a12andomizedcontrolledtrial；wynnek等，intjobes(lond)，30:1729-36，2006)。但是同样由于分子量偏小及dpp-iv的降解，胃泌酸调节素具有较短的半衰期。目前glp-1受体(glp-1r)和胰高血糖素受体(gcgr)的双效激动剂普遍都是基于胃泌酸调节素的，并且为了改善胃泌酸调节素的短效及酶解的缺陷而做了突变(胃泌酸调节素类似物)，且大都采用第二位丝氨酸ser突变为α-氨基异丁酸(aib)的方法，通过引入非天然氨基酸来抵抗dpp-iv的酶解。胃泌酸调节素类似物虽然表现出了初步的降糖及减脂效果，但是其作用机制仍不确切，胃泌酸调节素受体一直没有发现，目前仅仅是通过gcgr或glp-1r敲除的小鼠或者细胞试验验证胃泌酸调节素能与这2种受体结合而起作用。胰高血糖素(glucagon)是29个氨基酸的肽，其对应于前胰高血糖素原的53-81位氨基酸，序列如seqidno：42所示(c.g.fanelli等，nutrition,metabolism&cardiovasculardiseases(2006)16,s28-s34)。胰高血糖素受体活化已显示在啮齿类动物和人两者中增加能量消耗且减少食物摄入(habeggerk.m.等人，themetabolicactionsofglucagonrevisited,nat.rev.endocrinol.2010,6,689-697)并且这些效应在啮齿类动物中是稳定和持续的。胰高血糖素具有许多生理效应，例如通过刺激糖原分解和糖异生，增加低血糖状况下的血糖水平，调节肝酮生成，调节胆汁酸代谢和通过迷走神经的饱腹效应。在治疗上，胰高血糖素已经用于急性低血糖症，胰高血糖素受体激活减少食物摄取并促进动物和人的脂肪分解和体重减轻。术语“受体激动剂”可以定义为与受体结合且引发天然配体的通常应答的多肽、蛋白或其他小分子。“glp-1受体(glp-1r)激动剂”可以定义为与glp-1r结合且能够引发与天然glp-1相同或类似的特征性反应的多肽、蛋白或其他小分子。glp-1r激动剂通过完全或部分激活glp-1r，继而引起一系列细胞内的下游信号通路反应，产生相应的细胞活性：如β细胞分泌胰岛素；典型的glp-1r激动剂包括天然glp-1及其突变体、类似物，如埃塞那肽、利拉鲁肽(liraglutide)等。glp-1类似物：在本文中，“glp-1类似物”或“glp-1突变体”皆意为glp-1r激动剂，可互相通用。胰高血糖素受体(gcgr)激动剂:即glucagon受体激动剂，可以定义为与gcgr结合且能够引发与天然胰高血糖素(glucagon)相同或类似特征性反应的多肽、蛋白或其他小分子。gcgr激动剂通过完全或部分激活gcgr，继而引起一系列细胞内的下游信号通路反应，产生相应的细胞活性：如肝细胞糖原分解、糖质新生、脂肪酸氧化及生酮作用等。glucagon类似物：在本文中，“glucagon类似物”、“gcg类似物”、“glucagon突变体”和“gcg突变体”皆意为glucagon受体激动剂，可互相通用。gcgr/glp-1r双效活性肽：本发明的gcgr/glp-1r双效活性肽包括能同时激动glp-1r和gcgr的蛋白或多肽。如alessandropocai等报道的基于oxyntomodulin的双效激动剂(glucagon-likepeptide1/glucagonreceptordualagonismreversesobesityinmice，diabetes；58(10):2258-2266，2009)，或者richardd.dimarchi等报道的基于glucagon的双效激动剂(us9018164b2)。在本文中，“双效激动剂“或“双特异性活性蛋白”或“双效活性蛋白”皆同义。fgf21(fibroblastgrowthfactor21，成纤维细胞生长因子21)以及fgf15/19、fgf23，同属于fgf家族“内分泌”激素。fgf21是调节葡萄糖和脂质代谢的重要激素。与胰岛素调节的机制不同，fgf21通过上调节glut1的表达促进脂肪细胞中的葡萄糖摄取。fgf21与受体结合需跨膜蛋白β-klotho辅助，通过结合fgfr/β-klotho受体复合物从而刺激信号传导，激发肝、脂肪组织和胰腺的生物学作用。β-klotho在胰腺、肝脏、脂肪中选择性表达，这也解释了fgf21对这些组织作用的特异性(kurosuh等，tissue-specificexpressionofbetaklothoandfibroblastgrowthfactor(fgf)receptorisoformsdeterminesmetabolicactivityoffgf19andfgf21.jbiolchem282:26687-26695，2007；kharitonenkova等，(2008b)fgf-21/fgf-21receptorinteractionandactivationisdeterminedbybetaklotho.jcellphysiol215:1-7)。在辅助受体β-klotho存在下，fgf21可以结合并激活3种fgfr亚型(1c，2c和3c)，其他fgfr亚型，例如fgfr1b，2b和3b，由于不与β-klotho形成复合物，因此不作为fgf21受体。证据表明，在结合fgf21的fgfr受体中，fgfr1在调节fgf21活性中占主要地位。fgf21的n和c末端对于其生物活性非常重要的，其中n端结合fgfr，c端结合β-klotho(micanovicr,etal(2009)differentrolesofn-andc-terminiinthefunctionalactivityoffgf21.jcellphysiol219:227-234)。小鼠fgf21蛋白由210个氨基酸组成，氨基端有30个氨基酸组成的信号肽，人fgf21蛋白由209个氨基酸组成，氨基端有28个氨基酸组成的信号肽，人fgf21蛋白与小鼠具有约75％的同源性。fgf21主要表达于胰腺β细胞、肝脏、wat、骨骼肌，有明显的组织特异性。人fgf21在体内容易被脯氨酰肽酶(fap，一种丝氨酸蛋白酶)降解，在小鼠体内的半衰期为30min，猴子体内2h。多结构域：结构域是生物大分子中具有特异结构和独立功能的区域，特别指蛋白质中这样的区域。在球形蛋白中，结构域具有自己特定的三级结构,其功能不依赖于蛋白质分子中的其余部分，但是同一种蛋白质中不同结构域间常可通过不具二级结构的短序列连接起来。蛋白质中不同的结构域组成了多结构域。在本发明中，多结构域指包含了gcg类似物、fgf21及其类似物与fc形成的具有gcgr激动活性、glp-1r激动活性及fgf21活性的融合蛋白。二聚体：本发明所指的二聚体是通过免疫球蛋白的恒定区(fc)天然的非共价及共价作用而形成。如果没有其他特别指出，fc形成的二聚体皆为同二聚体，如本发明提供的二聚体所述。本发明中式i所述的活性蛋白，由于具有fc，因而都会形成二聚体。三效活性蛋白：在本文中，“三效激动活性蛋白”、“三活性激动活性蛋白”、“三特异性二聚体活性蛋白”等皆同义，可互换使用。ec50(concentrationfor50％ofmaximaleffect)是指某一药物或者物质在刺激其相应的生物学反应的50％时所需的浓度。ec50值越低，表明该药物或物质的刺激或激动能力越强，例如，更直观地可表现为引起的细胞内信号越强，从而诱导某激素产生的能力越佳。细胞生物学活性本发明的glp-1r和gcgr激动活性体外细胞活性测定都采用荧光素酶报告基因检测法。此法基于glp-1r和gcgr激动后能激活下游camp途径的原理。fgf21及其类似物的活性测定则是通过将fgf21r与β-klotho共转染同一个cho细胞，检测信号引起的荧光变化而获得。josephr.chabenne等和richardd.dimarchi等曾报道，在glucagon的c末端增加一段exendin-4的c末端小肽cex(gpssgappps)能使glp-1r的激动活性提高2倍左右(optimizationofthenativeglucagonsequenceformedicinalpurposes，jdiabetesscitechnol.4(6):1322–1331，2010及专利us9018164b2)，但是gcgr激动活性与glp-1r激动活性的比例仅达到35：1左右。另外，eversa等报道(eversa等，designofnovelexendin-baseddualglucagon-likepeptide1(glp-1)/glucagonreceptoragonists，jmedchem.；60(10):4293-4303.2017)在gcg类似物的c末端加上cex序列后，glp-1r激动活性反而下降了原来的3倍左右，gcg的活性下降了14倍左右(文章中表2，肽7和8)。在本发明的一个实施例中，将含gpssgappps或类似序列的gcg类似物进一步融合至fc链时，glp-1r激动活性提高了惊人的200倍以上(ec50约1.1nm)。而根据us9018164b2及josephr.chabenne等在相应专利及文献中披露的数据计算获得的gcg类似物，其glp-1r激动活性比例在增加gpssgappps或类似序列前后变化仅在2倍左右(如文章中天然glucagon的glp-1r激动活性百分比为0.7％，增加了gpssgappps序列后提高至1.6％)。就是说，在glucagon多肽的c末端增加gpssgappps序列并不会显著提高其glp-1r的激动活性。多结构域活性蛋白的稳定性天然glucagon有多处敏感的降解位点，包括第二位的dpp-iv降解位点，以及16-18位的srr位点。尽管有报道认为fc能提高活性蛋白的化学稳定性及血清稳定性，然而对于n端必须暴露的glp-1或glucagon类似物，fc的作用似乎是无法一概而论的。天然的glp-1或glucagon与fc融合后，仍能观察到其在37度血清条件下的明显降解。本发明在天然glucagon的基础上引入抵抗蛋白酶水解的突变，以增加其稳定性。这些突变体与fc融合后，稳定性进一步获得提高。目前几乎所有基于oxyntomodulin和glucagon设计开发的gcgr/glp-1r双效激动剂都在第二位上引入抵抗dpp-iv的突变，如l型突变为d型氨基酸(l-ser突变为d-ser)，或引入非天然氨基酸aib等(matthiash.等，unimolecularpolypharmacyfortreatmentofdiabetesandobesity，24：51–62,2016)。然而，在本发明的实施例中，符合式ii的且第二位保存天然l-ser的双效活性蛋白呈现出非常高的血清稳定性，在24小时仍并没有显著的dpp-iv降解的迹象，而没有融合fc的对应多肽则快速地被dpp-iv水解(表9)。本发明人制备了天然glucagon与fc融合的活性蛋白c001l13f8(seqidno.93)以及josephr.chabenne等报道的glucagon-cex与fc融合的活性蛋白c002l13f8(seqidno.94)作为对照验证是否fc融合提高了稳定性。然而，c001l13f8(seqidno.93)和c002l13f8(seqidno.94)均无呈现出明显的抵抗dpp-iv的迹象。虽然有报道指出结合在血清白蛋白(如hsa)上可能会有助于提高蛋白的稳定性(如利拉鲁肽)，然而如果第二位不进行突变，根本无法使半衰期持续12小时以上，即不可能支持一周一次的给药频率。而本发明提供的gcg类似物药代及药效试验显示足以支持一周一次的给药频率，而非普遍报道的一天一次(如结合白蛋白的利拉鲁肽)。天然氨基酸的保留进一步减低免疫原性的风险，避免了化学交联还使制备过程更简易方便。腹腔糖耐量测试(ipgtt)在其中一个实施例中，进行了ipgtt实验。施用了多结构域活性蛋白的小鼠在注射葡萄糖后，呈现出极平稳的血糖波动。dio小鼠的减重及食欲控制、药代实验gcgr激动剂具有潜在的减重效果已有多篇报道。然而天然glucagon由于易被降解且分子量极小，因此成药的潜力极小。目前glucagon类似物主要用于急性的低血糖症状。长效gcg类似物用于糖尿病患者减重的临床报道也不断涌现。众所周知，肥胖是导致糖尿病患者胰岛素抵抗的原因之一，而体重减轻量是评价一个降糖药物的重要指标。此外，本发明的多结构域活性蛋白在dio小鼠施用后，诱导了体重的显著降低。gcgr/glp-1r双效激动剂、fgf21及其类似物在降低血糖及脂质代谢中的作用已广为人知。stanislauss等报道(stanislauss等，anovelfcfgf21withimprovedresistancetoproteolysis,increasedaffinitytowardsβ-klothoandenhancedefficacyinmiceandcynomolgusmonkeysendocrinology.2017may1；158(5):1314-1327.)fc-fgf21类似物在3mg/kg(约30nm/kg)的剂量下，在连续4周给药后，体重减轻为15％以上。在本发明的实施例9中，30nm/kg剂量的三效活性蛋白减重达到约30％，而食欲则基本无明显变化。同样地，10nm/kg剂量时，减重也接近15％。另外，实施例10中的双效活性蛋白与长效fgf21类似物的组合物(a-la-f+f-lb-b)，也共同起到了协同作用的效果：联合给药的组合物可以减少35％或以上体重，然而等剂量的双效活性蛋白只能减轻不超过13％的体重，长效fgf21类似物对体重的减轻则在10％以下。临床应用展望在临床上，本发明的多重活性蛋白具有潜在的适合每周或以上施用一次的药物代谢动力学特性。剂量取决于施用频率和模式，受治疗的受试者的年龄、性别、重量和一般状况，治疗的状况和严重性，待治疗的任何伴随性疾病以及对于本领域技术人员显而易见的其他因素。同时，根据受治疗者的情况和其他病理状况，本发明的多重活性蛋白可以与一种或多种其他的治疗活性化合物或物质组合施用或应用，例如可以选择的其他的治疗活性化合物包括但不限于抗糖尿病药、抗高血脂药、抗肥胖药，抗高血压药和用于治疗起因于糖尿病或与糖尿病有关的并发症的试剂。代谢综合征与冠心病和血管斑块积累相关的其他病症风险增加相关，例如中风和外周血管疾病，成为粥样动脉硬化心血管病(ascvd)。患有代谢综合征的患者可自处于早期的胰岛素抗性状态发展成完全成熟的二型糖尿病，并且ascvd的风险进一步增加。不旨在受限于任何特定理论，胰岛素抗性、代谢综合征及血管疾病之间的关系可以涉及一种或多种共同发病机制，包括胰岛素刺激的血管舒张障碍、由氧化应力增强所致的胰岛素抗性相关性可用性降低，以及脂肪细胞衍生激素(诸如脂联素)异常(lteif,mather,can.j.cardiol.20(增刊b)：66b-76b，2004)本发明的活性蛋白还可用于治疗肥胖症。在一些方面中，本发明的活性蛋白通过降低食欲、减少食物摄取、降低患者体内脂肪水平、提高能量消耗等机制来治疗肥胖症。在一些潜在的实施方案中，本发明的活性蛋白可用于治疗非酒精性脂肪肝病(nafld)。nafld是指广谱肝脏疾病，范围自单纯脂肪肝(脂肪变性)至非酒精性脂肪变性肝炎(nash)至肝硬化(肝脏的不可逆晚期瘢痕形成)。nafld的所有病期均具有在肝脏细胞中的脂肪累积。单纯脂肪肝为某类型的脂肪、甘油三酯在肝脏细胞中异常积累，但无发炎或瘢痕形成。在nash中，脂肪累积与不同程度的肝脏发炎(肝炎)和瘢痕形成(纤维化)相关。发炎性细胞可破坏肝脏细胞(肝细胞坏死)。在术语“脂肪变性肝炎”和“脂肪变性坏死”中，脂肪变性是指脂肪浸润，肝炎是指肝脏中的炎症，并且坏死是指经破坏的肝脏细胞。nash可最终导致肝脏瘢痕形成(纤维化)且接着导致不可逆晚期瘢痕形成(肝硬化)，由nash导致的肝硬化为nafld谱内的最后且最严重的病期。在进一步描述本发明具体实施方式之前，应理解，本发明的保护范围不局限于下述特定的具体实施方案；还应当理解，本发明实施例中使用的术语是为了描述特定的具体实施方案，而不是为了限制本发明的保护范围。下列实施例中未注明具体条件的试验方法，通常按照常规条件，或者按照各制造商所建议的条件。当实施例给出数值范围时，应理解，除非本发明另有说明，每个数值范围的两个端点以及两个端点之间任何一个数值均可选用。除非另外定义，本发明中使用的所有技术和科学术语与本
技术领域：
技术人员通常理解的意义相同。除实施例中使用的具体方法、设备、材料外，根据本
技术领域：
的技术人员对现有技术的掌握及本发明的记载，还可以使用与本发明实施例中所述的方法、设备、材料相似或等同的现有技术的任何方法、设备和材料来实现本发明。除非另外说明，本发明中所公开的实验方法、检测方法、制备方法均采用本
技术领域：
常规的分子生物学、生物化学、染色质结构和分析、分析化学、细胞培养、重组dna技术及相关领域的常规技术。这些技术在现有文献中已有完善说明，具体可参见sambrook等molecularcloning：alaboratorymanual，secondedition，coldspringharborlaboratorypress，1989andthirdedition，2001；ausubel等，currentprotocolsinmolecularbiology，johnwiley&sons，newyork，1987andperiodicupdates；theseriesmethodsinenzymology，academicpress，sandiego；wolffe，chromatinstructureandfunction，thirdedition，academicpress，sandiego，1998；methodsinenzymology，vol.304，chromatin(p.m.wassarmananda.p.wolffe，eds.)，academicpress，sandiego，1999；和methodsinmolecularbiology，vol.119，chromatinprotocols(p.b.becker，ed.)humanapress，totowa，1999等。实施例1gcg类似物的筛选(胰高血糖类似物的筛选)天然glp-1的氨基酸序列如seqidno.1所示，具体为：haegtftsdvssylegqaakefiawlvkgrg。天然oxyntomodulin的氨基酸序列如seqidno.2所示，具体为：hsqgtftsdyskyldsrraqdfvqwlmntkrnrnnia。本发明的gcg类似物记为a，所述a为gcgr/glp-1r双效激动活性肽，选自所有能实现gcgr及glp-1r双效激动活性的肽链。所述a的结构式如式ii所示：hsqgtftsd-x10-s-x12-x13-x14-x15-x16-x17-x18-x19-x20-x21-f-x23-x24-wl-x27-x28-x29-x30-xz。其中，所述x10选自v、l或y之任一；所述x12选自s、e或k之任一；所述x13选自y或q之任一；所述x14选自l或m之任一；所述x15选自d或e之任一；所述x16选自s、e或g之任一；所述x17选自r、e或q之任一；所述x18选自r、e或a之任一；所述x19选自a或v之任一；所述x20选自q、r或k之任一；所述x21选自d、l或e之任一；所述x23选自v或i之任一；所述x24选自q、a或e之任一；所述x27选自m、k或v之任一；所述x28选自n或k之任一；所述x29选自g或t之任一；所述x30为g或缺失；所述xz不存在或选自gpssgappps(seqidno.3)、pssgappps(seqidno.4)、ssgappps(seqidno.5)、gpssgapps(seqidno.6)、pssgapps(seqidno.7)或krnrnnia(seqidno.8)之任一。表1中列举了部分本发明gcg类似物的氨基酸序列：表1实施例2双效活性蛋白a-la-f的制备本实施例中，由gcg类似物与连接链la及f融合而获得二聚体双效活性蛋白a-la-f。其中，a同实施例1中的a。具体地，所述a的结构式如式ii所示：hsqgtftsd-x10-s-x12-x13-x14-x15-x16-x17-x18-x19-x20-x21-f-x23-x24-wl-x27-x28-x29-x30-xz。其中，所述x10选自v、l或y之任一；所述x12选自s、e或k之任一；所述x13选自y或q之任一；所述x14选自l或m之任一；所述x15选自d或e之任一；所述x16选自s、e或g之任一；所述x17选自r、e或q之任一；所述x18选自r、e或a之任一；所述x19选自a或v之任一；所述x20选自q、r或k之任一；所述x21选自d、l或e之任一；所述x23选自v或i之任一；所述x24选自q、a或e之任一；所述x27选自m、k或v之任一；所述x28选自n或k之任一；所述x29选自g或t之任一；所述x30为g或缺失；所述xz不存在或选自gpssgappps(seqidno.3)、pssgappps(seqidno.4)、ssgappps(seqidno.5)、gpssgapps(seqidno.6)、pssgapps(seqidno.7)或krnrnnia(seqidno.8)之任一。所述f为长效蛋白单元，f可选自免疫球蛋白的完整fc部分、免疫球蛋白的fc部分的片段或免疫球蛋白的fc部分的突变体。所述f的氨基酸序列如seqidno.9-18所示。本发明将seqidno.9所示序列，简称为f1，具体为：epkscdkthtcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqvytlppsreemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspgk。本发明将seqidno.10所示序列，简称为f2，具体为：epkscdkthtcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqyastyrvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqvytlppsreemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspg。本发明将seqidno.11所示序列，简称为f3，具体为：dkthtcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqyastyrvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqvytlppsrdeltknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspgk。本发明将seqidno.12所示序列，简称为f4，具体为：dkthtcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqygstyrvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqvytlppsrdeltknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspg。本发明将seqidno.13所示序列，简称为f5，具体为：erkccvecppcpappvagpsvflfppkpkdtlmisrtpevtcvvvdvshedpevqfnwyvdgvevhnaktkpreeqfnstfrvvsvltvvhqdwlngkeykckvsnkglpssiektisktkgqprepqvytlppsreemtknqvsltclvkgfypsdiavewesngqpennykttppmldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspg。本发明将seqidno.14所示序列，简称为f6，具体为：eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgk。本发明将seqidno.15所示序列，简称为f7，具体为：eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfastyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgk。本发明将seqidno.16所示序列，简称为f8，具体为：eskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfastyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslg。本发明将seqidno.17所示序列，简称为f9，具体为：eskygppcppcpapeaaggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslg。本发明将seqidno.18所示序列，简称为f10，具体为：eskygppcppcpapeaaggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfastyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslg。la为连接链，所述连接链为一段合适长度的由甘氨酸(g)、丝氨酸(s)和/或丙氨酸(a)构成的柔性多肽，从而使相邻的蛋白质结构域可相对于彼此自由移动。当有必要保证所述两个相邻结构域空间上彼此互不干扰时，可以使用较长的连接链。所述连接链示例性的如(gs)n，(ggs)n，(ggsg)n，(gggs)na，(ggggs)na、(gggga)na等，n为1-10的整数。示例性的连接链可各自独立的选自表2。表2部分双效活性蛋白a-la-f的氨基酸序列如表3中所示：表3在知晓了a-la-f的氨基酸序列的基础上，本领域技术人员能够采用现有技术对其进行制备：由于带有fc序列，因此可通过高亲和力和高特异性的proteina树脂层析进行蛋白纯化，在这里仅示例性地给出一种可行的制备方法。制备过程如下：(1)根据蛋白序列及氨基酸密码子表，设计其dna序列。分别制备重组蛋白中a、la、f对应的多核苷酸dna片段，各dna片段均可由常规的固相合成技术合成拼接；(2)设计引物进行巢式pcr扩增，拼接a、la、f分别对应的dna片段，获得目的基因，pcr拼接技术(包括引物设计、pcr引入突变及酶切等)为本领域技术人员所熟知的公知技术。本领域技术人员应当知晓，本实施例的pcr拼接过程并非是唯一的方法，例如，通过基因合成也可以获得目的基因。成功获得目的基因后，将目的基因克隆至哺乳动物细胞表达载体ptt5(yvesdurocher)，转化大肠杆菌top10f’；阳性克隆鉴定后，接种于500mllb培养基中，过夜培养，离心收集菌体，使用omegaendo-freeplasmidmaxikit提取质粒；(3)转染hek293f细胞及细胞表达：取1.0mg质粒，使用freestyle293表达培养基(thermofisher)稀释至25ml；取3.0mgpei(线性，25kd)，使用freestyle293表达培养基稀释至25ml，加入到质粒溶液中，混匀，室温孵育30分钟；与此同时，取对数期生长的hek293f细胞(活率>95％)，计数；1100rpm，离心10分钟，弃上清；使用450mlfreestyle293表达培养基重悬细胞；pei质粒混合液孵育结束后，加入到细胞悬液中，37℃，5％co2，140rpm震荡培养；7小时后，使用1000ml293sfmii培养基(thermofisher)置换freestyle293表达培养基，继续培养7天；(4)重组蛋白的纯化：将细胞培养液以8000rpm，高速离心10min，得到上清上样到预先用平衡液(20mmpb，0.5mnacl，ph7)平衡好的proteina柱(博格隆(上海)生物技术有限公司)，100％洗脱(洗脱液为0.1mgly-hcl，ph3.0)；收集管中预先加入中和液为(1mtris-hcl，ph8.0)，收集洗脱样品；最后加中和液到洗脱样品体积的1/10，并采用常规bradford法测定蛋白浓度；(5)重组蛋白的理化性质鉴定：对纯化获得的重组蛋白进行sds-page电泳或氨基酸序列验证，均与预期一致。实施例3三效活性蛋白的制备本发明的三效活性蛋白，含有多结构域，具有三效激动活性。所述三效活性蛋白的结构式如式i所示：a-la-f-lb-b，其中a为gcgr/glp-1r双效激动活性肽，f为长效蛋白单元，b为天然fgf21或fgf21类似物，la为连接链，lb为连接链。式i中，所述a的结构式如式ii所示：hsqgtftsd-x10-s-x12-x13-x14-x15-x16-x17-x18-x19-x20-x21-f-x23-x24-wl-x27-x28-x29-x30-xz。其中，所述x10选自v、l或y之任一；所述x12选自s、e或k之任一；所述x13选自y或q之任一；所述x14选自l或m之任一；所述x15选自d或e之任一；所述x16选自s、e或g之任一；所述x17选自r、e或q之任一；所述x18选自r、e或a之任一；所述x19选自a或v之任一；所述x20选自q、r或k之任一；所述x21选自d、l或e之任一；所述x23选自v或i之任一；所述x24选自q、a或e之任一；所述x27选自m、k或v之任一；所述x28选自n或k之任一；所述x29选自g或t之任一；所述x30为g或缺失；所述xz不存在或选自gpssgappps(seqidno.3)、pssgappps(seqidno.4)、ssgappps(seqidno.5)、gpssgapps(seqidno.6)、pssgapps(seqidno.7)或krnrnnia(seqidno.8)之任一。式i中，所述f可选自免疫球蛋白的完整fc部分、免疫球蛋白的fc部分的片段或免疫球蛋白的fc部分的突变体，如seqidno.9-18所示。式i中，所述的b为天然fgf21(seqidno.136)或者fgf21类似物。所述b的结构式为：hpipdsspllqfggqvrqx19ylytddaqqtex31hleix36edgtvgx43ax45dqspesllqlx56alkpgviqilgvktsrflcqrpdgalygslhfdpeacsfrex98lledgynvyqseahglplhx118pgnx122sphrdpaprgpx134rflplpglppalpeppgilapqppdvgssdplx167mvx170x171sqx174rspsx179x180x181。其中，n端hpipdss可缺失或部分缺失；x19选自r、y、v、e或c；x31选自a或c；x36选自r或k；x43选自g或c；x45选自a、k、e或v；x56选自k、r、v或i；x98选自l、r或d；x118选自l或c；x122选自k或r；x134选自a或c；x167选自s、a或r；x170选自g或e；x171选自p或g；x174选自g、a或l；x179选自y、a或f；x180选自a或e；x181选自s、k或缺失。所述的fgf21类似物为与天然fgf21(seqidno.136)具有相同或相似生物学功能、且与天然fgf21(seqidno.136)同源性为80％以上的活性蛋白。优选地，所述fgf21类似物与天然fgf21(seqidno.136)同源性为85％以上；更优选地，所述fgf21类似物与天然fgf21(seqidno.136)同源性为90％以上；更优选地，所述fgf21类似物与天然fgf21(seqidno.136)同源性为95％以上。优选地，所述fgf21类似物如seqidno.137-148所示。天然fgf21及部分类似物的氨基酸序列详见表4：表4la不存在或为连接链，lb不存在或为连接链。当la和lb为连接链时，所述连接链为一段合适长度的由甘氨酸(g)、丝氨酸(s)和/或丙氨酸(a)构成的柔性多肽，从而使相邻的蛋白质结构域可相对于彼此自由移动。当有必要保证所述两个相邻结构域空间上彼此互不干扰时，可以使用较长的连接链。所述连接链示例性的如(gs)n，(ggs)n，(ggsg)n，(gggs)na，(ggggs)na、(gggga)na等，n为1-10的整数。示例性的连接链可各自独立的选自表2。在gcgr/glp-1r双效活性蛋白的基础上，在fc的c末端通过连接肽链融合fgf21或fgf21类似物，制备成如表5所述的示例性三效活性蛋白。表5在知晓了a-la-f-lb-b的氨基酸序列的基础上，本领域技术人员能够采用现有技术对其进行制备。由于带有fc序列，因此可通过高亲和力和高特异性的proteina树脂层析进行蛋白纯化。具体方法可参照实施例2中的制备方法。对纯化获得的重组蛋白进行sds-page电泳或氨基酸序列验证，均与预期一致。其中，图1为部分纯化样品的sds-page电泳图。实施例4融合fc的fgf21类似物的制备本实施例将代号为f9的fc与天然fgf21及代号为m1-m12的fgf21类似物融合，分别获得长效fgf21类似物，所述长效fgf21类似物的结构式为f-lb-b。所述f可选自免疫球蛋白的完整fc部分、免疫球蛋白的fc部分的片段或免疫球蛋白的fc部分的突变体。所述f的氨基酸序列可以如seqidno.9～18之任一所示。lb不存在或为连接链，当lb为连接链时，所述连接链包括含富含g、s和/或a的单元，示例性的如(gs)n，(ggs)n，(ggsg)n，(gggs)na，(ggggs)na、(gggga)na、等，n为1-10的整数，在一个优选的实施方案中，所述的连接链的氨基酸长度为5-26。示例性的连接链各自独立的选自表2。进一步地，所述连接链的氨基酸序列可如seqidno.19～41之任一所示。所述b为为天然fgf21(seqidno.136)或者fgf21类似物。所述b的结构式为：hpipdsspllqfggqvrqx19ylytddaqqtex31hleix36edgtvgx43ax45dqspesllqlx56alkpgviqilgvktsrflcqrpdgalygslhfdpeacsfrex98lledgynvyqseahglplhx118pgnx122sphrdpaprgpx134rflplpglppalpeppgilapqppdvgssdplx167mvx170x171sqx174rspsx179x180x181，其中，n端hpipdss可缺失或部分缺失；x19选自r、y、v、e或c；x31选自a或c；x36选自r或k；x43选自g或c；x45选自a、k、e或v；x56选自k、r、v或i；x98选自l、r或d；x118选自l或c；x122选自k或r；x134选自a或c；x167选自s、a或r；x170选自g或e；x171选自p或g；x174选自g、a或l；x179选自y、a或f；x180选自a或e；x181选自s、k或缺失。所述的fgf21类似物为与天然fgf21(seqidno.136)具有相同或相似生物学功能、且与天然fgf21(seqidno.136)同源性为80％以上的活性蛋白。优选地，所述fgf21类似物与天然fgf21(seqidno.136)同源性为85％以上；更优选地，所述fgf21类似物与天然fgf21(seqidno.136)同源性为90％以上；更优选地，所述fgf21类似物与天然fgf21(seqidno.136)同源性为95％以上。示例性地，所述的fgf21类似物可选自如us20140213512、us8188040、us9493530、wo2016114633、us20150291677、us9422353、us8541369、us7622445、us7576190、us20070142278、us9006400或us20130252884等专利或专利申请中所描述的fgf21类似物或突变体。所述fgf21类似物如seqidno.137-148所示。所述长效fgf21类似物氨基酸序列可分别如seqidno.209-seqidno.221所示。根据蛋白质序列合成dna并亚克隆至重组表达载体为本
技术领域：
的常规方法，同实施例2，转染hek293f细胞及细胞表达。同样，由于带有fc序列，分离纯化的过程也可参照实施例2。f9l10w序列如seqidno.209所示：eskygppcppcpapeaaggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgggggaggggaggggahpipdsspllqfggqvrqrylytddaqqteahleiredgtvggaadqspesllqlkalkpgviqilgvktsrflcqrpdgalygslhfdpeacsfrellledgynvyqseahglplhlpgnksphrdpaprgparflplpglppalpeppgilapqppdvgssdplsmvgpsqgrspsyas。f9l10m1序列如seqidno.210所示：eskygppcppcpapeaaggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgggggaggggaggggahpipdsspllqfggqvrqrylytddaqqteahleiredgtvggaadqspesllqlkalkpgviqilgvktsrflcqrpdgalygslhfdpeacsfrerlledgynvyqseahglplhlpgnksphrdpaprgparflplpglppalpeppgilapqppdvgssdplsmvggsqgrspsyes。f9l10m2序列如seqidno.211所示：eskygppcppcpapeaaggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgggggaggggaggggahpipdsspllqfggqvrqrylytddaqqteahleiredgtvggaadqspesllqlkalkpgviqilgvktsrflcqrpdgalygslhfdpeacsfrerlledgynvyqseahglplhcpgnksphrdpaprgpcrflplpglppalpeppgilapqppdvgssdplsmvggsqgrspsyes。f9l10m3序列如seqidno.212所示：eskygppcppcpapeaaggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgggggaggggaggggadsspllqfggqvrqrylytddaqqteahleiredgtvggaadqspesllqlkalkpgviqilgvktsrflcqrpdgalygslhfdpeacsfrellledgynvyqseahglplhcpgnksphrdpaprgpcrflplpglppalpeppgilapqppdvgssdplamvgpsqgrspsyas。f9l10m4序列如seqidno.213所示：eskygppcppcpapeaaggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgggggaggggaggggahpipdsspllqfggqvrqrylytddaqqteahleiredgtvggaadqspesllqlkalkpgviqilgvktsrflcqrpdgalygslhfdpeacsfrerlledgynvyqseahglplhcpgnksphrdpaprgpcrflplpglppalpeppgilapqppdvgssdplamvggsqgrspsyes。f9l10m5序列如seqidno.214所示：eskygppcppcpapeaaggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgggggaggggaggggahpipdsspllqfggqvrqrylytddaqqteahleiredgtvggaedqspesllqlkalkpgviqilgvktsrflcqrpdgalygslhfdpeacsfrerlledgynvyqseahglplhcpgnksphrdpaprgpcrflplpglppalpeppgilapqppdvgssdplsmvggsqgrspsyes。f9l10m6序列如seqidno.215所示：eskygppcppcpapeaaggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgggggaggggaggggahpipdsspllqfggqvrqrylytddaqqteahleiredgtvggaadqspesllqlkalkpgviqilgvktsrflcqrpdgalygslhfdpeacsfrerlledgynvyqseahglplhcpgnksphrdpaprgpcrflplpglppalpeppgilapqppdvgssdplsmvepsqgrspsyas。f9l10m7序列如seqidno.216所示：eskygppcppcpapeaaggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgggggaggggaggggahpipdsspllqfggqvrqeylytddaqqteahleiredgtvggaadqspesllqlkalkpgviqilgvktsrflcqrpdgalygslhfdpeacsfrerlledgynvyqseahglplhlpgnksphrdpaprgparflplpglppalpeppgilapqppdvgssdplsmvggsqgrspsyes。f9l10m8序列如seqidno.217所示：eskygppcppcpapeaaggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgggggaggggaggggahpipdsspllqfggqvrqrylytddaqqteahleiredgtvggaadqspesllqlkalkpgviqilgvktsrflcqrpdgalygslhfdpeacsfrerlledgynvyqseahglplhlpgnksphrdpaprgparflplpglppalpeppgilapqppdvgssdplsmvggsqgrspsaas。f9l10m9序列如seqidno.218所示：eskygppcppcpapeaaggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgggggaggggaggggahpipdsspllqfggqvrqrylytddaqqteahleiredgtvggaadqspesllqlkalkpgviqilgvktsrflcqrpdgalygslhfdpeacsfrerlledgynvyqseahglplhcpgnksphrdpaprgpcrflplpglppalpeppgilapqppdvgssdplamvggsqgrspsyas。f9l10m10序列如seqidno.219所示：eskygppcppcpapeaaggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgggggaggggaggggadsspllqfggqvrqrylytddaqqteahleiredgtvggaadqspesllqlkalkpgviqilgvktsrflcqrpdgalygslhfdpeacsfrerlledgynvyqseahglplhcpgnksphrdpaprgpcrflplpglppalpeppgilapqppdvgssdplamvggsqgrspsyas。f9l10m11序列如seqidno.220所示：eskygppcppcpapeaaggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgggggaggggaggggahpipdsspllqfggqvrqrylytddaqqteahleiredgtvggaadqspesllqlkalkpgviqilgvktsrflcqrpdgalygslhfdpeacsfrerlledgynvyqseahglplhlpgnksphrdpaprgparflplpglppalpeppgilapqppdvgssdplamvggsqgrspsyes。f9l10m12序列如seqidno.221所示：eskygppcppcpapeaaggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslslgggggaggggaggggahpipdsspllqfggqvrqrylytddaqqteahleiredgtvggaadqspesllqlkalkpgviqilgvktsrflcqrpdgalygslhfdpeacsfrerlledgynvyqseahglplhcpgnksphrdpaprgpcrflplpglppalpeppgilapqppdvgssdplamvggsqgrspsyas。实施例5体外细胞活性检测将实施例2中获得的双效活性蛋白进行体外活性测定，包括glp-1r激动活性检测和gcgr激动活性检测。glp-1r激动活性检测：glp-1r激动活性检测采用荧光素酶报告基因检测法(jonathanwday等：natchembiol.2009oct；5(10):749-57)。将人源glp-1r基因克隆至哺乳动物细胞表达质粒pcdna3.1中，构建成重组表达质粒pcdna3.1-glp-1r，同时荧光素酶(luciferase)全长基因克隆至pcre质粒上得到pcre-luc重组质粒。pcdna3.1-glp-1r和pcre-luc质粒按摩尔比1:10的比例转染cho细胞，筛选稳转表达株，获得重组cho/glp-1r稳转细胞株。在9-cm细胞培养皿中用含10％fbs和300μg/mlg418的dmem/f12培养基培养细胞，等汇合度至90％左右时，弃去培养上清，加入2ml胰酶消化3min后，加入2ml含10％fbs和300μg/mlg418的dmem/f12培养基中和，转移至15ml离心管中，1000rpm离心5min后，弃去上清，加入2ml含10％fbs和300μg/mlg418的dmem/f12培养基重悬，计数。用含10％fbs的dmem/f12培养基稀释细胞至3×105，96孔板中每孔铺100μl，即5×104/孔，贴壁后换成含0.2％fbs的dmem/f12培养基培养。铺在96孔板的细胞弃去上清后，将纯化的重组蛋白(表6、表7)或天然glucagon(杭州中肽生化有限公司，gluc-004)与天然glp-1(杭州中肽生化有限公司,gluc-016b)作为对照，用含0.1％fbs的dmem/f12培养基稀释至一系列指定浓度，加入到细胞培养孔中，100μl/孔，刺激6h后检测。根据萤光素酶报告检测试剂盒(lucifersaereporterkit，raybiotech,cat:68-lucir-s200)说明书进行检测。gcgr激动活性检测方法：gcgr激动活性检测同样也采用类似的荧光素酶报告基因检测法。将gcgr基因克隆至哺乳动物细胞表达质粒pcdna3.1中，构建成重组表达质粒pcdna3.1-gcgr，与pcre-luc重组质粒共转染hek293t细胞并筛选稳转细胞株hek293t/gcgr的构建同上。fgf21活性检测方法：fgf21活性测定采用文献类似方法并做适当改进(xuj等，polyethyleneglycolmodifiedfgf21engineeredtomaximizepotencyandminimizevacuoleformation，bioconjugchem.；24(6):915-25，2013)。pcr扩增嘌呤霉素抗性基因pac，克隆到pcdna3.1(+)，替换原有的g418抗性基因。pcr扩增gal4dbd-elk1、ires、klb(β-klotho)基因，依次克隆到pcdna-puro质粒上，构建质粒pcdna-gal4dbd-elk1-ires-klb-puro用于细胞转染筛选。质粒采用omegaendo-freeplasmidmidikit提取备用。细胞转染过程如下：hek293t细胞铺6孔板，每孔3x105个细胞，培养过夜。opti-mem培养基洗涤细胞两次后，加入2mlopti-mem培养基。按照如下比例配制细胞转染试剂：lipofectamine2000(6μl)：pfr-luc(4.6μg)：pcdna-gal4dbd-elk1-ires-klb-puro(1μg)。静置20min后，缓慢加入到6孔板中，边加边混匀。培养6h后换dmem+10％fbs培养基，37℃，5％co2继续培养。筛选获得具有fgf21活性响应的稳转细胞株。细胞长满培养皿后，胰酶消化，制备细胞悬液(1x105细胞/ml,dmem+5％fbs+1μg/mlpuromycin)，铺96孔板，每孔100μl，过夜培养。添加梯度浓度的待测样品，作用6h，使用luciferasereporterassaykit(68-lucifr-s200)进行荧光检测。部分双效活性蛋白的活性测定结果如表6、表7所示：表6说明：表中蛋白编号按照如下规则：多肽代号+连接链代号+fc代号，如c240l13f4，表示c240多肽与代号为f4的iggfc通过代号为l13的连接链融合。a.为gcg类似物与fc链之间插入gpssgappps或类似序列(又称为cex序列，在本发明中为seqidno.3-8之任一)前后的glp-1r激动活性比例。b.为根据us9018164b2表2中披露的天然glucagon与glucagoncex的glp-1r激动活性数据计算获得的比例。c.为根据josephr.chabenne等(josephr.chabenne等，optimizationofthenativeglucagonsequenceformedicinalpurposes，jdiabetesscitechnol.4(6):1322–1331，2010)文章中表1披露的天然glucagon与glucagoncex的glp-1r激动活性数据计算获得的比例。如表6-表8所示，当把含cex延伸肽的序列通过(ggggs)3a(seqidno.31)与f(seqidno.16)融合制备成二聚体后，对glp-1r的激动活性提高了200倍以上，而对gcgr的激动活性则无明显差异。表7三效活性蛋白的活性检测实施例3制备的三效活性蛋白活性结果如表8所示：表8表中蛋白编号按照如下规则：多肽代号+连接链代号+fc代号+连接链代号+fgf21突变体代号，如c209l13f4l13m9，表示c209多肽与代号为f4的iggfc通过代号为l13的连接链融合，再进一步与代号为m9的fgf21突变体通过代号为l13的连接链融合。实施例6三效活性蛋白的dpp-iv耐酶稳定性将纯化的三效活性蛋白5um溶解于10mm的hepes缓冲液(含0.05mg/mlbsa中，加入终浓度为10nm的重组dpp-iv酶，于37℃温浴24小时后，检测体外gcgr细胞活性检测。活性保留率＝(dpp-iv酶处理后活性/处理前活性)×100％。本实施例中采用了第二位引入非天然氨基酸aib或d-ser的gcg类似物作为对照：gdsergs：h-d-ser-qgtftsdyskyldsqaaqdfvqwlmnggpssgappps(seqidno.134)；gaibgs：h-aib-qgtftsdyskyldsqaaqdfvqwlmnggpssgappps(seqidno.135)；c364(seqidno.70)、c382(seqidno.57)、c495(seqidno.53)、c462(seqidno.66)、c225(seqidno.47)及c209(seqidno.71)作为本实施例中稳定性实验的对照。结果如表9所示：表9实施例7三效活性蛋白的血清稳定性试验体外细胞检测法：(1)取三效活性蛋白，先超滤浓缩，再用20mmpbph7.4稀释到1.6mg/ml，除菌过滤后，血清(fbs，gemini900-108，a97e00g)稀释10倍，混匀，分装到无菌离心管中；(2)另外取glucagon(seqidno：42，杭州中肽生化有限公司，gluc-004)，稀释到0.2mg/ml，除菌过滤后，血清稀释10倍，混匀，分装到无菌离心管中；(3)上述样品1-2管于-20度冻存作为对照，另几管置37℃培养箱，于不同时间点取样检测gcgr激动活性；(4)hek293t/gcgr细胞传代两次后铺96孔板，检测样品活性。残留活性：以0小时的活性值为100％，后续时间点测得的值与之相比而获得。除了c002l13f4l13w外，同表9中的结果相似，各三效活性蛋白的血清稳定性无显著差异。示例性的三效活性蛋白相对活性随着时间的变化如图2a-c所示。实施例8正常icr小鼠的葡萄糖耐量试验(ipgtt)正常icr小鼠分组，每组8只。禁食过夜，尾部采血(记为t＝0分钟血糖样)，皮下注射三效活性蛋白(40nmol/kg，醋酸盐缓冲液)、组合物(联合给药组)或生理盐水pbs。联合给药组在给药前预先混合(各40nmol/kg，醋酸盐缓冲液)。15分钟后腹腔注射葡萄糖(2克/千克体重)，并在t＝30分钟、t＝60分钟、t＝120分钟和t＝240分钟测量血液葡萄糖水平。在实验期间动物仍禁食以防止食物摄取的干扰。结果如图3所示。实施例9三效活性蛋白连续给药在诱导肥胖(dio)小鼠中的药效研究7周龄雄性c57bl/6j雄性小鼠给予高脂饲料(60％kcalfromfat)继续饲养16周(共23周)，到体重约为55g时进行试验。饲养条件：12h光照/12h黑暗，自由采食，单笼饲养，给药前一天根据体重和体重生长曲线对小鼠进行分组(8只/组)，第二天皮下给药处理。根据表10所示，活性蛋白按照10nmol/千克体重或30nmol/千克体重的剂量给药，4天一次；阴性对照组按5ul/克体重注射生理盐水(pbs)；阳性对照组注射利拉鲁肽(30nmol/千克体重)，每天一次给药，连续给药28天，每天测量小鼠体重及进食量。最后一次给药后的第5天处死。眼眶取血。将血浆标本储存在-80℃。计算每组动物给药前及处死时的平均体重变化。体重变化结果如图4所示；总摄食量的变化如图5所示。表10样品seqidno.剂量(nm)c002l13f8l10w14910c495l13f8l10m216010c382l13f8l10m216710c462l13f8l10m218010c495l13f8l10m216030c382l13f8l10m216730c462l13f8l10m218030实施例10联合给药在诱导肥胖(dio)小鼠中的药效研究本实施例与实施例9的不同之处在于双效活性蛋白与长效fgf21类似物采用复方的形式联合给药。7周龄雄性c57bl/6j雄性小鼠给予高脂饲料(60％kcalfromfat)继续饲养16周(共23周)，到体重约为55g时进行试验。饲养条件：12h光照/12h黑暗，自由采食，单笼饲养，给药前一天根据体重和体重生长曲线对小鼠进行分组(8只/组)，第二天皮下给药处理。双效活性蛋白与长效fgf21类似物在给药前根据表11所示剂量混合，按照15nmol/千克体重或30nmol/千克体重的剂量给药，4天一次；阴性对照组按5ul/克体重注射生理盐水(pbs)；阳性对照组注射利拉鲁肽(30nmol/千克体重)，每天一次给药，连续给药28天，每天测量小鼠体重及进食量。最后一次给药后的第5天处死。眼眶取血。将血浆标本储存在-80℃。计算每组动物给药前及处死时的平均体重变化。体重变化结果如图6所示；总摄食量的变化如图7所示。表11样品seqidno.剂量(nm)c495l13f8+f9l10m1106、210各30c495l13f8+f9l10m2106、211各30c382l13f8+f9l10m298、211各30c382l13f8+f9l10m398、212各30c462l13f8+f9l10m1114、210各30c462l13f8+f9l10m2114、211各30c462l13f8+f9l10m3114、212各30c462l13f8114、30c382l13f898、30c495l13f8106、30f9l10m121030f9l10m221130f9l10m321230以上所述，仅为本发明的较佳实施例，并非对本发明任何形式上和实质上的限制，应当指出，对于本
技术领域：
的普通技术人员，在不脱离本发明方法的前提下，还将可以做出若干改进和补充，这些改进和补充也应视为本发明的保护范围。凡熟悉本专业的技术人员，在不脱离本发明的精神和范围的情况下，当可利用以上所揭示的技术内容而做出的些许更动、修饰与演变的等同变化，均为本发明的等效实施例；同时，凡依据本发明的实质技术对上述实施例所作的任何等同变化的更动、修饰与演变，均仍属于本发明的技术方案的范围内。序列表<110>浙江道尔生物科技有限公司<120>一种治疗代谢疾病的多结构域活性蛋白<130>173864<160>221<170>siposequencelisting1.0<210>1<211>31<212>prt<213>人工序列(artificialsequence)<400>1hisalagluglythrphethrseraspvalsersertyrleuglugly151015glnalaalalysglupheilealatrpleuvallysglyarggly202530<210>2<211>37<212>prt<213>人工序列(artificialsequence)<400>2hisserglnglythrphethrserasptyrserlystyrleuaspser151015argargalaglnaspphevalglntrpleumetasnthrlysargasn202530argasnasnileala35<210>3<211>10<212>prt<213>人工序列(artificialsequence)<400>3glyproserserglyalaproproproser1510<210>4<211>9<212>prt<213>人工序列(artificialsequence)<400>4proserserglyalaproproproser15<210>5<211>8<212>prt<213>人工序列(artificialsequence)<400>5serserglyalaproproproser15<210>6<211>9<212>prt<213>人工序列(artificialsequence)<400>6glyproserserglyalaproproser15<210>7<211>8<212>prt<213>人工序列(artificialsequence)<400>7proserserglyalaproproser15<210>8<211>8<212>prt<213>人工序列(artificialsequence)<400>8lysargasnargasnasnileala15<210>9<211>232<212>prt<213>人工序列(artificialsequence)<400>9gluprolyssercysasplysthrhisthrcysproprocysproala151015progluleuleuglyglyproservalpheleupheproprolyspro202530lysaspthrleumetileserargthrprogluvalthrcysvalval354045valaspvalserhisgluaspprogluvallyspheasntrptyrval505560aspglyvalgluvalhisasnalalysthrlysproarggluglugln65707580tyrasnserthrtyrargvalvalservalleuthrvalleuhisgln859095asptrpleuasnglylysglutyrlyscyslysvalserasnlysala100105110leuproalaproileglulysthrileserlysalalysglyglnpro115120125arggluproglnvaltyrthrleuproproserarggluglumetthr130135140lysasnglnvalserleuthrcysleuvallysglyphetyrproser145150155160aspilealavalglutrpgluserasnglyglnprogluasnasntyr165170175lysthrthrproprovalleuaspseraspglyserphepheleutyr180185190serlysleuthrvalasplysserargtrpglnglnglyasnvalphe195200205sercysservalmethisglualaleuhisasnhistyrthrglnlys210215220serleuserleuserproglylys225230<210>10<211>231<212>prt<213>人工序列(artificialsequence)<400>10gluprolyssercysasplysthrhisthrcysproprocysproala151015progluleuleuglyglyproservalpheleupheproprolyspro202530lysaspthrleumetileserargthrprogluvalthrcysvalval354045valaspvalserhisgluaspprogluvallyspheasntrptyrval505560aspglyvalgluvalhisasnalalysthrlysproarggluglugln65707580tyralaserthrtyrargvalvalservalleuthrvalleuhisgln859095asptrpleuasnglylysglutyrlyscyslysvalserasnlysala100105110leuproalaproileglulysthrileserlysalalysglyglnpro115120125arggluproglnvaltyrthrleuproproserarggluglumetthr130135140lysasnglnvalserleuthrcysleuvallysglyphetyrproser145150155160aspilealavalglutrpgluserasnglyglnprogluasnasntyr165170175lysthrthrproprovalleuaspseraspglyserphepheleutyr180185190serlysleuthrvalasplysserargtrpglnglnglyasnvalphe195200205sercysservalmethisglualaleuhisasnhistyrthrglnlys210215220serleuserleuserprogly225230<210>11<211>227<212>prt<213>人工序列(artificialsequence)<400>11asplysthrhisthrcysproprocysproalaprogluleuleugly151015glyproservalpheleupheproprolysprolysaspthrleumet202530ileserargthrprogluvalthrcysvalvalvalaspvalserhis354045gluaspprogluvallyspheasntrptyrvalaspglyvalgluval505560hisasnalalysthrlysproargglugluglntyralaserthrtyr65707580argvalvalservalleuthrvalleuhisglnasptrpleuasngly859095lysglutyrlyscyslysvalserasnlysalaleuproalaproile100105110glulysthrileserlysalalysglyglnproarggluproglnval115120125tyrthrleuproproserargaspgluleuthrlysasnglnvalser130135140leuthrcysleuvallysglyphetyrproseraspilealavalglu145150155160trpgluserasnglyglnprogluasnasntyrlysthrthrpropro165170175valleuaspseraspglyserphepheleutyrserlysleuthrval180185190asplysserargtrpglnglnglyasnvalphesercysservalmet195200205hisglualaleuhisasnhistyrthrglnlysserleuserleuser210215220proglylys225<210>12<211>226<212>prt<213>人工序列(artificialsequence)<400>12asplysthrhisthrcysproprocysproalaprogluleuleugly151015glyproservalpheleupheproprolysprolysaspthrleumet202530ileserargthrprogluvalthrcysvalvalvalaspvalserhis354045gluaspprogluvallyspheasntrptyrvalaspglyvalgluval505560hisasnalalysthrlysproargglugluglntyrglyserthrtyr65707580argvalvalservalleuthrvalleuhisglnasptrpleuasngly859095lysglutyrlyscyslysvalserasnlysalaleuproalaproile100105110glulysthrileserlysalalysglyglnproarggluproglnval115120125tyrthrleuproproserargaspgluleuthrlysasnglnvalser130135140leuthrcysleuvallysglyphetyrproseraspilealavalglu145150155160trpgluserasnglyglnprogluasnasntyrlysthrthrpropro165170175valleuaspseraspglyserphepheleutyrserlysleuthrval180185190asplysserargtrpglnglnglyasnvalphesercysservalmet195200205hisglualaleuhisasnhistyrthrglnlysserleuserleuser210215220progly225<210>13<211>227<212>prt<213>人工序列(artificialsequence)<400>13gluarglyscyscysvalglucysproprocysproalaproproval151015alaglyproservalpheleupheproprolysprolysaspthrleu202530metileserargthrprogluvalthrcysvalvalvalaspvalser354045hisgluaspprogluvalglnpheasntrptyrvalaspglyvalglu505560valhisasnalalysthrlysproargglugluglnpheasnserthr65707580pheargvalvalservalleuthrvalvalhisglnasptrpleuasn859095glylysglutyrlyscyslysvalserasnlysglyleuproserser100105110ileglulysthrileserlysthrlysglyglnproarggluprogln115120125valtyrthrleuproproserarggluglumetthrlysasnglnval130135140serleuthrcysleuvallysglyphetyrproseraspilealaval145150155160glutrpgluserasnglyglnprogluasnasntyrlysthrthrpro165170175prometleuaspseraspglyserphepheleutyrserlysleuthr180185190valasplysserargtrpglnglnglyasnvalphesercysserval195200205methisglualaleuhisasnhistyrthrglnlysserleuserleu210215220serprogly225<210>14<211>229<212>prt<213>人工序列(artificialsequence)<400>14gluserlystyrglyproprocysproprocysproalaprogluphe151015leuglyglyproservalpheleupheproprolysprolysaspthr202530leumetileserargthrprogluvalthrcysvalvalvalaspval354045serglngluaspprogluvalglnpheasntrptyrvalaspglyval505560gluvalhisasnalalysthrlysproargglugluglnpheasnser65707580thrtyrargvalvalservalleuthrvalleuhisglnasptrpleu859095asnglylysglutyrlyscyslysvalserasnlysglyleuproser100105110serileglulysthrileserlysalalysglyglnproargglupro115120125glnvaltyrthrleuproproserglngluglumetthrlysasngln130135140valserleuthrcysleuvallysglyphetyrproseraspileala145150155160valglutrpgluserasnglyglnprogluasnasntyrlysthrthr165170175proprovalleuaspseraspglyserphepheleutyrserargleu180185190thrvalasplysserargtrpglngluglyasnvalphesercysser195200205valmethisglualaleuhisasnhistyrthrglnlysserleuser210215220leuserleuglylys225<210>15<211>229<212>prt<213>人工序列(artificialsequence)<400>15gluserlystyrglyproprocysproprocysproalaprogluphe151015leuglyglyproservalpheleupheproprolysprolysaspthr202530leumetileserargthrprogluvalthrcysvalvalvalaspval354045serglngluaspprogluvalglnpheasntrptyrvalaspglyval505560gluvalhisasnalalysthrlysproargglugluglnphealaser65707580thrtyrargvalvalservalleuthrvalleuhisglnasptrpleu859095asnglylysglutyrlyscyslysvalserasnlysglyleuproser100105110serileglulysthrileserlysalalysglyglnproargglupro115120125glnvaltyrthrleuproproserglngluglumetthrlysasngln130135140valserleuthrcysleuvallysglyphetyrproseraspileala145150155160valglutrpgluserasnglyglnprogluasnasntyrlysthrthr165170175proprovalleuaspseraspglyserphepheleutyrserargleu180185190thrvalasplysserargtrpglngluglyasnvalphesercysser195200205valmethisglualaleuhisasnhistyrthrglnlysserleuser210215220leuserleuglylys225<210>16<211>228<212>prt<213>人工序列(artificialsequence)<400>16gluserlystyrglyproprocysproprocysproalaprogluphe151015leuglyglyproservalpheleupheproprolysprolysaspthr202530leumetileserargthrprogluvalthrcysvalvalvalaspval354045serglngluaspprogluvalglnpheasntrptyrvalaspglyval505560gluvalhisasnalalysthrlysproargglugluglnphealaser65707580thrtyrargvalvalservalleuthrvalleuhisglnasptrpleu859095asnglylysglutyrlyscyslysvalserasnlysglyleuproser100105110serileglulysthrileserlysalalysglyglnproargglupro115120125glnvaltyrthrleuproproserglngluglumetthrlysasngln130135140valserleuthrcysleuvallysglyphetyrproseraspileala145150155160valglutrpgluserasnglyglnprogluasnasntyrlysthrthr165170175proprovalleuaspseraspglyserphepheleutyrserargleu180185190thrvalasplysserargtrpglngluglyasnvalphesercysser195200205valmethisglualaleuhisasnhistyrthrglnlysserleuser210215220leuserleugly225<210>17<211>228<212>prt<213>人工序列(artificialsequence)<400>17gluserlystyrglyproprocysproprocysproalaprogluala151015alaglyglyproservalpheleupheproprolysprolysaspthr202530leumetileserargthrprogluvalthrcysvalvalvalaspval354045serglngluaspprogluvalglnpheasntrptyrvalaspglyval505560gluvalhisasnalalysthrlysproargglugluglnpheasnser65707580thrtyrargvalvalservalleuthrvalleuhisglnasptrpleu859095asnglylysglutyrlyscyslysvalserasnlysglyleuproser100105110serileglulysthrileserlysalalysglyglnproargglupro115120125glnvaltyrthrleuproproserglngluglumetthrlysasngln130135140valserleuthrcysleuvallysglyphetyrproseraspileala145150155160valglutrpgluserasnglyglnprogluasnasntyrlysthrthr165170175proprovalleuaspseraspglyserphepheleutyrserargleu180185190thrvalasplysserargtrpglngluglyasnvalphesercysser195200205valmethisglualaleuhisasnhistyrthrglnlysserleuser210215220leuserleugly225<210>18<211>228<212>prt<213>人工序列(artificialsequence)<400>18gluserlystyrglyproprocysproprocysproalaprogluala151015alaglyglyproservalpheleupheproprolysprolysaspthr202530leumetileserargthrprogluvalthrcysvalvalvalaspval354045serglngluaspprogluvalglnpheasntrptyrvalaspglyval505560gluvalhisasnalalysthrlysproargglugluglnphealaser65707580thrtyrargvalvalservalleuthrvalleuhisglnasptrpleu859095asnglylysglutyrlyscyslysvalserasnlysglyleuproser100105110serileglulysthrileserlysalalysglyglnproargglupro115120125glnvaltyrthrleuproproserglngluglumetthrlysasngln130135140valserleuthrcysleuvallysglyphetyrproseraspileala145150155160valglutrpgluserasnglyglnprogluasnasntyrlysthrthr165170175proprovalleuaspseraspglyserphepheleutyrserargleu180185190thrvalasplysserargtrpglngluglyasnvalphesercysser195200205valmethisglualaleuhisasnhistyrthrglnlysserleuser210215220leuserleugly225<210>19<211>5<212>prt<213>人工序列(artificialsequence)<400>19glyglyglyglyser15<210>20<211>5<212>prt<213>人工序列(artificialsequence)<400>20glyglyglyglyala15<210>21<211>8<212>prt<213>人工序列(artificialsequence)<400>21glyglyglyserglyglyglyser15<210>22<211>8<212>prt<213>人工序列(artificialsequence)<400>22glyserglyserglyserglyser15<210>23<211>10<212>prt<213>人工序列(artificialsequence)<400>23glyglyglyglyserglyglyglyglyser1510<210>24<211>10<212>prt<213>人工序列(artificialsequence)<400>24glyglyglyglyalaglyglyglyglyala1510<210>25<211>12<212>prt<213>人工序列(artificialsequence)<400>25glyglyserglyglyglyserglyglyglyglyser1510<210>26<211>12<212>prt<213>人工序列(artificialsequence)<400>26glyglyserglyglyglyalaglyglyglyglyser1510<210>27<211>15<212>prt<213>人工序列(artificialsequence)<400>27glyglyglyglyserglyglyglyglyserglyglyglyglyser151015<210>28<211>15<212>prt<213>人工序列(artificialsequence)<400>28glyglyglyglyalaglyglyglyglyalaglyglyglyglyala151015<210>29<211>16<212>prt<213>人工序列(artificialsequence)<400>29glyglyserglyglyglyglyserglyglyglyglyserglyglyala151015<210>30<211>16<212>prt<213>人工序列(artificialsequence)<400>30glyglyglyglyalaglyglyglyglyalaglyglyglyglyalaala151015<210>31<211>16<212>prt<213>人工序列(artificialsequence)<400>31glyglyglyglyserglyglyglyglyserglyglyglyglyserala151015<210>32<211>16<212>prt<213>人工序列(artificialsequence)<400>32glyglyglyglyalaglyglyglyglyalaglyglyglyglyalaser151015<210>33<211>17<212>prt<213>人工序列(artificialsequence)<400>33glyserglyglyglyglyserglyglyglyglyserglyglyglygly151015ser<210>34<211>20<212>prt<213>人工序列(artificialsequence)<400>34glyglyglyglyalaglyglyglyglyalaglyglyglyglyalagly151015glyglyglyala20<210>35<211>20<212>prt<213>人工序列(artificialsequence)<400>35glyglyglyglyserglyglyglyglyserglyglyglyglysergly151015glyglyglyser20<210>36<211>22<212>prt<213>人工序列(artificialsequence)<400>36glyserglyglyglyglyserglyglyglyglyserglyglyglygly151015serglyglyglyglyser20<210>37<211>25<212>prt<213>人工序列(artificialsequence)<400>37glyglyglyglyserglyglyglyglyserglyglyglyglysergly151015glyglyglyserglyglyglyglyser2025<210>38<211>26<212>prt<213>人工序列(artificialsequence)<400>38glyglyglyglyserglyglyglyglyserglyglyglyglysergly151015glyglyglyserglyglyglyglyserala2025<210>39<211>30<212>prt<213>人工序列(artificialsequence)<400>39glyglyglyglyserglyglyglyglyserglyglyglyglysergly151015glyglyglyserglyglyglyglyserglyglyglyglyser202530<210>40<211>35<212>prt<213>人工序列(artificialsequence)<400>40glyglyglyglyserglyglyglyglyserglyglyglyglysergly151015glyglyglyserglyglyglyglyserglyglyglyglyserglygly202530glyglyser35<210>41<211>40<212>prt<213>人工序列(artificialsequence)<400>41glyglyglyglyserglyglyglyglyserglyglyglyglysergly151015glyglyglyserglyglyglyglyserglyglyglyglyserglygly202530glyglyserglyglyglyglyser3540<210>42<211>29<212>prt<213>人工序列(artificialsequence)<400>42hisserglnglythrphethrserasptyrserlystyrleuaspser151015argargalaglnaspphevalglntrpleumetasnthr2025<210>43<211>39<212>prt<213>人工序列(artificialsequence)<400>43hisserglnglythrphethrserasptyrserlystyrleuaspser151015argargalaglnaspphevalglntrpleumetasnthrglyproser202530serglyalaproproproser35<210>44<211>39<212>prt<213>人工序列(artificialsequence)<400>44hisserglnglythrphethrserasptyrserlystyrleuaspglu151015argalaalaglnaspphevalglntrpleumetasnglyglyproser202530serglyalaproproproser35<210>45<211>39<212>prt<213>人工序列(artificialsequence)<400>45hisserglnglythrphethrserasptyrserlystyrleuaspglu151015argglualaglnaspphevalglntrpleumetasnglyglyproser202530serglyalaproproproser35<210>46<211>39<212>prt<213>人工序列(artificialsequence)<400>46hisserglnglythrphethrserasptyrserlystyrleuaspser151015argalaalaglnaspphevalglntrpleumetasnglyglyproser202530serglyalaproproproser35<210>47<211>39<212>prt<213>人工序列(artificialsequence)<400>47hisserglnglythrphethrserasptyrserlystyrleuaspglu151015argalaalaglnaspphevalglntrpleumetasnthrglyproser202530serglyalaproproproser35<210>48<211>39<212>prt<213>人工序列(artificialsequence)<400>48hisserglnglythrphethrserasptyrserlystyrleuaspser151015argglualaglnaspphevalglntrpleumetasnglyglyproser202530serglyalaproproproser35<210>49<211>39<212>prt<213>人工序列(artificialsequence)<400>49hisserglnglythrphethrserasptyrserlystyrleuaspser151015argalaalaglnaspphevalglntrpleumetasnthrglyproser202530serglyalaproproproser35<210>50<211>39<212>prt<213>人工序列(artificialsequence)<400>50hisserglnglythrphethrserasptyrserlystyrleuaspser151015glnglualaglnaspphevalglntrpleumetasnglyglyproser202530serglyalaproproproser35<210>51<211>39<212>prt<213>人工序列(artificialsequence)<400>51hisserglnglythrphethrserasptyrserlystyrleuaspgly151015argalaalaglnaspphevalglntrpleumetasnthrglyproser202530serglyalaproproproser35<210>52<211>39<212>prt<213>人工序列(artificialsequence)<400>52hisserglnglythrphethrserasptyrserlystyrleuaspglu151015glnalaalaglnaspphevalglntrpleumetasnthrglyproser202530serglyalaproproproser35<210>53<211>39<212>prt<213>人工序列(artificialsequence)<400>53hisserglnglythrphethrserasptyrserlystyrleuaspglu151015glnalaalaglnaspphevalglntrpleumetasnglyglyproser202530serglyalaproproproser35<210>54<211>37<212>prt<213>人工序列(artificialsequence)<400>54hisserglnglythrphethrserasptyrserlystyrleuaspglu151015glnalaalaglnaspphevalglntrpleumetasnglyproserser202530glyalaproproser35<210>55<211>38<212>prt<213>人工序列(artificialsequence)<400>55hisserglnglythrphethrserasptyrserlystyrleuaspglu151015glnalaalaglnaspphevalglntrpleumetasnglyproserser202530glyalaproproproser35<210>56<211>38<212>prt<213>人工序列(artificialsequence)<400>56hisserglnglythrphethrserasptyrserlystyrleuaspglu151015glnglualaglnaspphevalglntrpleumetasnglyproserser202530glyalaproproproser35<210>57<211>39<212>prt<213>人工序列(artificialsequence)<400>57hisserglnglythrphethrserasptyrserlystyrleuaspser151015glnalaalaglnaspphevalglntrpleumetasnglyglyproser202530serglyalaproproproser35<210>58<211>39<212>prt<213>人工序列(artificialsequence)<400>58hisserglnglythrphethrserasptyrserlystyrleuaspser151015glnalaalaglnaspphevalglntrpleumetasnthrglyproser202530serglyalaproproproser35<210>59<211>38<212>prt<213>人工序列(artificialsequence)<400>59hisserglnglythrphethrserasptyrserlystyrleuaspser151015glnalaalaglnaspphevalglntrpleumetasnthrglyproser202530serglyalaproproser35<210>60<211>38<212>prt<213>人工序列(artificialsequence)<400>60hisserglnglythrphethrserasptyrserlystyrleuaspser151015glnalaalaglnaspphevalglntrpleumetasnglyproserser202530glyalaproproproser35<210>61<211>39<212>prt<213>人工序列(artificialsequence)<400>61hisserglnglythrphethrserasptyrserlystyrleuaspser151015gluargalaglnaspphevalglntrpleumetasnthrglyproser202530serglyalaproproproser35<210>62<211>39<212>prt<213>人工序列(artificialsequence)<400>62hisserglnglythrphethrserasptyrserlystyrleuaspgly151015gluargalaglnaspphevalglntrpleumetasnthrglyproser202530serglyalaproproproser35<210>63<211>39<212>prt<213>人工序列(artificialsequence)<400>63hisserglnglythrphethrserasptyrserlystyrleuaspgly151015gluglualaglnaspphevalglntrpleumetasnthrglyproser202530serglyalaproproproser35<210>64<211>39<212>prt<213>人工序列(artificialsequence)<400>64hisserglnglythrphethrserasptyrserlystyrleuaspgly151015argglualaglnaspphevalglntrpleumetasnglyglyproser202530serglyalaproproproser35<210>65<211>39<212>prt<213>人工序列(artificialsequence)<400>65hisserglnglythrphethrserasptyrserlystyrleuaspglu151015glualaalaglnaspphevalglntrpleumetasnthrglyproser202530serglyalaproproproser35<210>66<211>39<212>prt<213>人工序列(artificialsequence)<400>66hisserglnglythrphethrserasptyrserlystyrleuaspglu151015glualaalaglnaspphevalglntrpleumetasnglyglyproser202530serglyalaproproproser35<210>67<211>39<212>prt<213>人工序列(artificialsequence)<400>67hisserglnglythrphethrserasptyrserlystyrleuaspglu151015gluargalaglnaspphevalglntrpleumetasnthrglyproser202530serglyalaproproproser35<210>68<211>39<212>prt<213>人工序列(artificialsequence)<400>68hisserglnglythrphethrserasptyrserlystyrleuaspser151015glnargalaglnaspphevalglntrpleumetasnthrglyproser202530serglyalaproproproser35<210>69<211>39<212>prt<213>人工序列(artificialsequence)<400>69hisserglnglythrphethrserasptyrserlystyrleuaspgly151015glnglualaglnaspphevalglntrpleumetasnglyglyproser202530serglyalaproproproser35<210>70<211>39<212>prt<213>人工序列(artificialsequence)<400>70hisserglnglythrphethrserasptyrserlystyrleuaspgly151015glnalaalaglnaspphevalglntrpleumetasnglyglyproser202530serglyalaproproproser35<210>71<211>39<212>prt<213>人工序列(artificialsequence)<400>71hisserglnglythrphethrserasptyrserlystyrleuaspser151015glualaalaglnaspphevalglntrpleumetasnglyglyproser202530serglyalaproproproser35<210>72<211>39<212>prt<213>人工序列(artificialsequence)<400>72hisserglnglythrphethrserasptyrserlystyrleuaspgly151015glualaalaglnaspphevalglntrpleumetasnglyglyproser202530serglyalaproproproser35<210>73<211>38<212>prt<213>人工序列(artificialsequence)<400>73hisserglnglythrphethrserasptyrserlystyrleuaspglu151015argalaalaglnaspphevalglntrpleuleuaspglyproserser202530glyalaproproproser35<210>74<211>39<212>prt<213>人工序列(artificialsequence)<400>74hisserglnglythrphethrseraspleuserlysglnmetaspser151015argalaalaglnasppheileglutrpleulysasnglyglyproser202530serglyalaproproproser35<210>75<211>39<212>prt<213>人工序列(artificialsequence)<400>75hisserglnglythrphethrseraspleuserlysglnmetaspser151015argglualaglnasppheileglutrpleulysasnthrglyproser202530serglyalaproproproser35<210>76<211>39<212>prt<213>人工序列(artificialsequence)<400>76hisserglnglythrphethrserasptyrserlysglnmetaspser151015glnargalaglnaspphevalglntrpleumetasnglyglyproser202530serglyalaproproproser35<210>77<211>39<212>prt<213>人工序列(artificialsequence)<400>77hisserglnglythrphethrserasptyrserlysglnleuaspser151015glnargalaglnaspphevalglntrpleumetasnglyglyproser202530serglyalaproproproser35<210>78<211>39<212>prt<213>人工序列(artificialsequence)<400>78hisserglnglythrphethrserasptyrserlystyrleuaspglu151015glualaalaglnasppheileglutrpleulysasnthrglyproser202530serglyalaproproproser35<210>79<211>39<212>prt<213>人工序列(artificialsequence)<400>79hisserglnglythrphethrserasptyrsersertyrleuaspglu151015glualaalaglnasppheileglutrpleulysasnthrglyproser202530serglyalaproproproser35<210>80<211>38<212>prt<213>人工序列(artificialsequence)<400>80hisserglnglythrphethrseraspvalserlystyrleugluser151015argalaalaglnaspphevalglntrpmetasnglyglyproserser202530glyalaproproproser35<210>81<211>38<212>prt<213>人工序列(artificialsequence)<400>81hisserglnglythrphethrseraspleuserlystyrleugluglu151015glnalaalaglnaspphevalglntrpmetasnglyglyproserser202530glyalaproproproser35<210>82<211>38<212>prt<213>人工序列(artificialsequence)<400>82hisserglnglythrphethrseraspleuserlystyrleuglugly151015glnalaalaglnaspphevalglntrpmetasnglyglyproserser202530glyalaproproproser35<210>83<211>38<212>prt<213>人工序列(artificialsequence)<400>83hisserglnglythrphethrseraspleuserlystyrleuglugly151015glnalaalaglnaspphevalglntrpmetasnthrglyproserser202530glyalaproproproser35<210>84<211>30<212>prt<213>人工序列(artificialsequence)<400>84hisserglnglythrphethrserasptyrserglutyrleuaspser151015gluargalaargaspphevalalatrpleuglualaglygly202530<210>85<211>29<212>prt<213>人工序列(artificialsequence)<400>85hisserglnglythrphethrserasptyrserlystyrleugluglu151015glualavalargleupheileglntrpleumetasnthr2025<210>86<211>39<212>prt<213>人工序列(artificialsequence)<400>86hisserglnglythrphethrserasptyrserlystyrleugluglu151015glualavalargleupheileglntrpleumetasnglyglyproser202530serglyalaproproproser35<210>87<211>37<212>prt<213>人工序列(artificialsequence)<400>87hisserglnglythrphethrserasptyrserlystyrleuaspser151015glnalaalaglnaspphevalglntrpleumetasnthrlysargasn202530argasnasnileala35<210>88<211>37<212>prt<213>人工序列(artificialsequence)<400>88hisserglnglythrphethrserasptyrserlystyrleuaspser151015glualaalaglnaspphevalglntrpleumetasnthrlysargasn202530argasnasnileala35<210>89<211>37<212>prt<213>人工序列(artificialsequence)<400>89hisserglnglythrphethrserasptyrserlystyrleuaspser151015glnglualaglnaspphevalglntrpleumetasnthrlysargasn202530argasnasnileala35<210>90<211>37<212>prt<213>人工序列(artificialsequence)<400>90hisserglnglythrphethrserasptyrserlystyrleuaspglu151015glnalaalaglnaspphevalglntrpleumetasnthrlysargasn202530argasnasnileala35<210>91<211>37<212>prt<213>人工序列(artificialsequence)<400>91hisserglnglythrphethrserasptyrserlysglnmetaspser151015glnargalaglnaspphevalglntrpleumetasnthrlysargasn202530argasnasnileala35<210>92<211>37<212>prt<213>人工序列(artificialsequence)<400>92hisserglnglythrphethrseraspleuserlysglnmetaspser151015argalaalaglnasppheileglutrpleulysasnthrlysargasn202530argasnasnileala35<210>93<211>273<212>prt<213>人工序列(artificialsequence)<400>93hisserglnglythrphethrserasptyrserlystyrleuaspser151015argargalaglnaspphevalglntrpleumetasnthrglyglygly202530glyserglyglyglyglyserglyglyglyglyseralagluserlys354045tyrglyproprocysproprocysproalaproglupheleuglygly505560proservalpheleupheproprolysprolysaspthrleumetile65707580serargthrprogluvalthrcysvalvalvalaspvalserglnglu859095aspprogluvalglnpheasntrptyrvalaspglyvalgluvalhis100105110asnalalysthrlysproargglugluglnphealaserthrtyrarg115120125valvalservalleuthrvalleuhisglnasptrpleuasnglylys130135140glutyrlyscyslysvalserasnlysglyleuproserserileglu145150155160lysthrileserlysalalysglyglnproarggluproglnvaltyr165170175thrleuproproserglngluglumetthrlysasnglnvalserleu180185190thrcysleuvallysglyphetyrproseraspilealavalglutrp195200205gluserasnglyglnprogluasnasntyrlysthrthrproproval210215220leuaspseraspglyserphepheleutyrserargleuthrvalasp225230235240lysserargtrpglngluglyasnvalphesercysservalmethis245250255glualaleuhisasnhistyrthrglnlysserleuserleuserleu260265270gly<210>94<211>283<212>prt<213>人工序列(artificialsequence)<400>94hisserglnglythrphethrserasptyrserlystyrleuaspser151015argargalaglnaspphevalglntrpleumetasnthrglyproser202530serglyalaproproproserglyglyglyglyserglyglyglygly354045serglyglyglyglyseralagluserlystyrglyproprocyspro505560procysproalaproglupheleuglyglyproservalpheleuphe65707580proprolysprolysaspthrleumetileserargthrprogluval859095thrcysvalvalvalaspvalserglngluaspprogluvalglnphe100105110asntrptyrvalaspglyvalgluvalhisasnalalysthrlyspro115120125argglugluglnphealaserthrtyrargvalvalservalleuthr130135140valleuhisglnasptrpleuasnglylysglutyrlyscyslysval145150155160serasnlysglyleuproserserileglulysthrileserlysala165170175lysglyglnproarggluproglnvaltyrthrleuproprosergln180185190gluglumetthrlysasnglnvalserleuthrcysleuvallysgly195200205phetyrproseraspilealavalglutrpgluserasnglyglnpro210215220gluasnasntyrlysthrthrproprovalleuaspseraspglyser225230235240phepheleutyrserargleuthrvalasplysserargtrpglnglu245250255glyasnvalphesercysservalmethisglualaleuhisasnhis260265270tyrthrglnlysserleuserleuserleugly275280<210>95<211>273<212>prt<213>人工序列(artificialsequence)<400>95hisserglnglythrphethrserasptyrserlystyrleuaspglu151015argalaalaglnaspphevalglntrpleumetasnglyglyglygly202530glyserglyglyglyglyserglyglyglyglyseralagluserlys354045tyrglyproprocysproprocysproalaproglupheleuglygly505560proservalpheleupheproprolysprolysaspthrleumetile65707580serargthrprogluvalthrcysvalvalvalaspvalserglnglu859095aspprogluvalglnpheasntrptyrvalaspglyvalgluvalhis100105110asnalalysthrlysproargglugluglnphealaserthrtyrarg115120125valvalservalleuthrvalleuhisglnasptrpleuasnglylys130135140glutyrlyscyslysvalserasnlysglyleuproserserileglu145150155160lysthrileserlysalalysglyglnproarggluproglnvaltyr165170175thrleuproproserglngluglumetthrlysasnglnvalserleu180185190thrcysleuvallysglyphetyrproseraspilealavalglutrp195200205gluserasnglyglnprogluasnasntyrlysthrthrproproval210215220leuaspseraspglyserphepheleutyrserargleuthrvalasp225230235240lysserargtrpglngluglyasnvalphesercysservalmethis245250255glualaleuhisasnhistyrthrglnlysserleuserleuserleu260265270gly<210>96<211>283<212>prt<213>人工序列(artificialsequence)<400>96hisserglnglythrphethrserasptyrserlystyrleuaspglu151015argalaalaglnaspphevalglntrpleumetasnglyglyproser202530serglyalaproproproserglyglyglyglyserglyglyglygly354045serglyglyglyglyseralagluserlystyrglyproprocyspro505560procysproalaproglupheleuglyglyproservalpheleuphe65707580proprolysprolysaspthrleumetileserargthrprogluval859095thrcysvalvalvalaspvalserglngluaspprogluvalglnphe100105110asntrptyrvalaspglyvalgluvalhisasnalalysthrlyspro115120125argglugluglnphealaserthrtyrargvalvalservalleuthr130135140valleuhisglnasptrpleuasnglylysglutyrlyscyslysval145150155160serasnlysglyleuproserserileglulysthrileserlysala165170175lysglyglnproarggluproglnvaltyrthrleuproprosergln180185190gluglumetthrlysasnglnvalserleuthrcysleuvallysgly195200205phetyrproseraspilealavalglutrpgluserasnglyglnpro210215220gluasnasntyrlysthrthrproprovalleuaspseraspglyser225230235240phepheleutyrserargleuthrvalasplysserargtrpglnglu245250255glyasnvalphesercysservalmethisglualaleuhisasnhis260265270tyrthrglnlysserleuserleuserleugly275280<210>97<211>273<212>prt<213>人工序列(artificialsequence)<400>97hisserglnglythrphethrserasptyrserlystyrleuaspser151015glnalaalaglnaspphevalglntrpleumetasnglyglyglygly202530glyserglyglyglyglyserglyglyglyglyseralagluserlys354045tyrglyproprocysproprocysproalaproglupheleuglygly505560proservalpheleupheproprolysprolysaspthrleumetile65707580serargthrprogluvalthrcysvalvalvalaspvalserglnglu859095aspprogluvalglnpheasntrptyrvalaspglyvalgluvalhis100105110asnalalysthrlysproargglugluglnphealaserthrtyrarg115120125valvalservalleuthrvalleuhisglnasptrpleuasnglylys130135140glutyrlyscyslysvalserasnlysglyleuproserserileglu145150155160lysthrileserlysalalysglyglnproarggluproglnvaltyr165170175thrleuproproserglngluglumetthrlysasnglnvalserleu180185190thrcysleuvallysglyphetyrproseraspilealavalglutrp195200205gluserasnglyglnprogluasnasntyrlysthrthrproproval210215220leuaspseraspglyserphepheleutyrserargleuthrvalasp225230235240lysserargtrpglngluglyasnvalphesercysservalmethis245250255glualaleuhisasnhistyrthrglnlysserleuserleuserleu260265270gly<210>98<211>283<212>prt<213>人工序列(artificialsequence)<400>98hisserglnglythrphethrserasptyrserlystyrleuaspser151015glnalaalaglnaspphevalglntrpleumetasnglyglyproser202530serglyalaproproproserglyglyglyglyserglyglyglygly354045serglyglyglyglyseralagluserlystyrglyproprocyspro505560procysproalaproglupheleuglyglyproservalpheleuphe65707580proprolysprolysaspthrleumetileserargthrprogluval859095thrcysvalvalvalaspvalserglngluaspprogluvalglnphe100105110asntrptyrvalaspglyvalgluvalhisasnalalysthrlyspro115120125argglugluglnphealaserthrtyrargvalvalservalleuthr130135140valleuhisglnasptrpleuasnglylysglutyrlyscyslysval145150155160serasnlysglyleuproserserileglulysthrileserlysala165170175lysglyglnproarggluproglnvaltyrthrleuproprosergln180185190gluglumetthrlysasnglnvalserleuthrcysleuvallysgly195200205phetyrproseraspilealavalglutrpgluserasnglyglnpro210215220gluasnasntyrlysthrthrproprovalleuaspseraspglyser225230235240phepheleutyrserargleuthrvalasplysserargtrpglnglu245250255glyasnvalphesercysservalmethisglualaleuhisasnhis260265270tyrthrglnlysserleuserleuserleugly275280<210>99<211>273<212>prt<213>人工序列(artificialsequence)<400>99hisserglnglythrphethrserasptyrserlystyrleuaspser151015argalaalaglnaspphevalglntrpleumetasnglyglyglygly202530glyserglyglyglyglyserglyglyglyglyseralagluserlys354045tyrglyproprocysproprocysproalaproglupheleuglygly505560proservalpheleupheproprolysprolysaspthrleumetile65707580serargthrprogluvalthrcysvalvalvalaspvalserglnglu859095aspprogluvalglnpheasntrptyrvalaspglyvalgluvalhis100105110asnalalysthrlysproargglugluglnphealaserthrtyrarg115120125valvalservalleuthrvalleuhisglnasptrpleuasnglylys130135140glutyrlyscyslysvalserasnlysglyleuproserserileglu145150155160lysthrileserlysalalysglyglnproarggluproglnvaltyr165170175thrleuproproserglngluglumetthrlysasnglnvalserleu180185190thrcysleuvallysglyphetyrproseraspilealavalglutrp195200205gluserasnglyglnprogluasnasntyrlysthrthrproproval210215220leuaspseraspglyserphepheleutyrserargleuthrvalasp225230235240lysserargtrpglngluglyasnvalphesercysservalmethis245250255glualaleuhisasnhistyrthrglnlysserleuserleuserleu260265270gly<210>100<211>283<212>prt<213>人工序列(artificialsequence)<400>100hisserglnglythrphethrserasptyrserlystyrleuaspser151015argalaalaglnaspphevalglntrpleumetasnglyglyproser202530serglyalaproproproserglyglyglyglyserglyglyglygly354045serglyglyglyglyseralagluserlystyrglyproprocyspro505560procysproalaproglupheleuglyglyproservalpheleuphe65707580proprolysprolysaspthrleumetileserargthrprogluval859095thrcysvalvalvalaspvalserglngluaspprogluvalglnphe100105110asntrptyrvalaspglyvalgluvalhisasnalalysthrlyspro115120125argglugluglnphealaserthrtyrargvalvalservalleuthr130135140valleuhisglnasptrpleuasnglylysglutyrlyscyslysval145150155160serasnlysglyleuproserserileglulysthrileserlysala165170175lysglyglnproarggluproglnvaltyrthrleuproprosergln180185190gluglumetthrlysasnglnvalserleuthrcysleuvallysgly195200205phetyrproseraspilealavalglutrpgluserasnglyglnpro210215220gluasnasntyrlysthrthrproprovalleuaspseraspglyser225230235240phepheleutyrserargleuthrvalasplysserargtrpglnglu245250255glyasnvalphesercysservalmethisglualaleuhisasnhis260265270tyrthrglnlysserleuserleuserleugly275280<210>101<211>273<212>prt<213>人工序列(artificialsequence)<400>101hisserglnglythrphethrserasptyrserlystyrleuaspglu151015glnalaalaglnaspphevalglntrpleumetasnthrglyglygly202530glyserglyglyglyglyserglyglyglyglyseralagluserlys354045tyrglyproprocysproprocysproalaproglupheleuglygly505560proservalpheleupheproprolysprolysaspthrleumetile65707580serargthrprogluvalthrcysvalvalvalaspvalserglnglu859095aspprogluvalglnpheasntrptyrvalaspglyvalgluvalhis100105110asnalalysthrlysproargglugluglnphealaserthrtyrarg115120125valvalservalleuthrvalleuhisglnasptrpleuasnglylys130135140glutyrlyscyslysvalserasnlysglyleuproserserileglu145150155160lysthrileserlysalalysglyglnproarggluproglnvaltyr165170175thrleuproproserglngluglumetthrlysasnglnvalserleu180185190thrcysleuvallysglyphetyrproseraspilealavalglutrp195200205gluserasnglyglnprogluasnasntyrlysthrthrproproval210215220leuaspseraspglyserphepheleutyrserargleuthrvalasp225230235240lysserargtrpglngluglyasnvalphesercysservalmethis245250255glualaleuhisasnhistyrthrglnlysserleuserleuserleu260265270gly<210>102<211>283<212>prt<213>人工序列(artificialsequence)<400>102hisserglnglythrphethrserasptyrserlystyrleuaspglu151015glnalaalaglnaspphevalglntrpleumetasnthrglyproser202530serglyalaproproproserglyglyglyglyserglyglyglygly354045serglyglyglyglyseralagluserlystyrglyproprocyspro505560procysproalaproglupheleuglyglyproservalpheleuphe65707580proprolysprolysaspthrleumetileserargthrprogluval859095thrcysvalvalvalaspvalserglngluaspprogluvalglnphe100105110asntrptyrvalaspglyvalgluvalhisasnalalysthrlyspro115120125argglugluglnphealaserthrtyrargvalvalservalleuthr130135140valleuhisglnasptrpleuasnglylysglutyrlyscyslysval145150155160serasnlysglyleuproserserileglulysthrileserlysala165170175lysglyglnproarggluproglnvaltyrthrleuproprosergln180185190gluglumetthrlysasnglnvalserleuthrcysleuvallysgly195200205phetyrproseraspilealavalglutrpgluserasnglyglnpro210215220gluasnasntyrlysthrthrproprovalleuaspseraspglyser225230235240phepheleutyrserargleuthrvalasplysserargtrpglnglu245250255glyasnvalphesercysservalmethisglualaleuhisasnhis260265270tyrthrglnlysserleuserleuserleugly275280<210>103<211>273<212>prt<213>人工序列(artificialsequence)<400>103hisserglnglythrphethrserasptyrserlystyrleuaspglu151015argalaalaglnaspphevalglntrpleumetasnthrglyglygly202530glyserglyglyglyglyserglyglyglyglyseralagluserlys354045tyrglyproprocysproprocysproalaproglupheleuglygly505560proservalpheleupheproprolysprolysaspthrleumetile65707580serargthrprogluvalthrcysvalvalvalaspvalserglnglu859095aspprogluvalglnpheasntrptyrvalaspglyvalgluvalhis100105110asnalalysthrlysproargglugluglnphealaserthrtyrarg115120125valvalservalleuthrvalleuhisglnasptrpleuasnglylys130135140glutyrlyscyslysvalserasnlysglyleuproserserileglu145150155160lysthrileserlysalalysglyglnproarggluproglnvaltyr165170175thrleuproproserglngluglumetthrlysasnglnvalserleu180185190thrcysleuvallysglyphetyrproseraspilealavalglutrp195200205gluserasnglyglnprogluasnasntyrlysthrthrproproval210215220leuaspseraspglyserphepheleutyrserargleuthrvalasp225230235240lysserargtrpglngluglyasnvalphesercysservalmethis245250255glualaleuhisasnhistyrthrglnlysserleuserleuserleu260265270gly<210>104<211>283<212>prt<213>人工序列(artificialsequence)<400>104hisserglnglythrphethrserasptyrserlystyrleuaspglu151015argalaalaglnaspphevalglntrpleumetasnthrglyproser202530serglyalaproproproserglyglyglyglyserglyglyglygly354045serglyglyglyglyseralagluserlystyrglyproprocyspro505560procysproalaproglupheleuglyglyproservalpheleuphe65707580proprolysprolysaspthrleumetileserargthrprogluval859095thrcysvalvalvalaspvalserglngluaspprogluvalglnphe100105110asntrptyrvalaspglyvalgluvalhisasnalalysthrlyspro115120125argglugluglnphealaserthrtyrargvalvalservalleuthr130135140valleuhisglnasptrpleuasnglylysglutyrlyscyslysval145150155160serasnlysglyleuproserserileglulysthrileserlysala165170175lysglyglnproarggluproglnvaltyrthrleuproprosergln180185190gluglumetthrlysasnglnvalserleuthrcysleuvallysgly195200205phetyrproseraspilealavalglutrpgluserasnglyglnpro210215220gluasnasntyrlysthrthrproprovalleuaspseraspglyser225230235240phepheleutyrserargleuthrvalasplysserargtrpglnglu245250255glyasnvalphesercysservalmethisglualaleuhisasnhis260265270tyrthrglnlysserleuserleuserleugly275280<210>105<211>273<212>prt<213>人工序列(artificialsequence)<400>105hisserglnglythrphethrserasptyrserlystyrleuaspglu151015glnalaalaglnaspphevalglntrpleumetasnglyglyglygly202530glyserglyglyglyglyserglyglyglyglyseralagluserlys354045tyrglyproprocysproprocysproalaproglupheleuglygly505560proservalpheleupheproprolysprolysaspthrleumetile65707580serargthrprogluvalthrcysvalvalvalaspvalserglnglu859095aspprogluvalglnpheasntrptyrvalaspglyvalgluvalhis100105110asnalalysthrlysproargglugluglnphealaserthrtyrarg115120125valvalservalleuthrvalleuhisglnasptrpleuasnglylys130135140glutyrlyscyslysvalserasnlysglyleuproserserileglu145150155160lysthrileserlysalalysglyglnproarggluproglnvaltyr165170175thrleuproproserglngluglumetthrlysasnglnvalserleu180185190thrcysleuvallysglyphetyrproseraspilealavalglutrp195200205gluserasnglyglnprogluasnasntyrlysthrthrproproval210215220leuaspseraspglyserphepheleutyrserargleuthrvalasp225230235240lysserargtrpglngluglyasnvalphesercysservalmethis245250255glualaleuhisasnhistyrthrglnlysserleuserleuserleu260265270gly<210>106<211>283<212>prt<213>人工序列(artificialsequence)<400>106hisserglnglythrphethrserasptyrserlystyrleuaspglu151015glnalaalaglnaspphevalglntrpleumetasnglyglyproser202530serglyalaproproproserglyglyglyglyserglyglyglygly354045serglyglyglyglyseralagluserlystyrglyproprocyspro505560procysproalaproglupheleuglyglyproservalpheleuphe65707580proprolysprolysaspthrleumetileserargthrprogluval859095thrcysvalvalvalaspvalserglngluaspprogluvalglnphe100105110asntrptyrvalaspglyvalgluvalhisasnalalysthrlyspro115120125argglugluglnphealaserthrtyrargvalvalservalleuthr130135140valleuhisglnasptrpleuasnglylysglutyrlyscyslysval145150155160serasnlysglyleuproserserileglulysthrileserlysala165170175lysglyglnproarggluproglnvaltyrthrleuproprosergln180185190gluglumetthrlysasnglnvalserleuthrcysleuvallysgly195200205phetyrproseraspilealavalglutrpgluserasnglyglnpro210215220gluasnasntyrlysthrthrproprovalleuaspseraspglyser225230235240phepheleutyrserargleuthrvalasplysserargtrpglnglu245250255glyasnvalphesercysservalmethisglualaleuhisasnhis260265270tyrthrglnlysserleuserleuserleugly275280<210>107<211>273<212>prt<213>人工序列(artificialsequence)<400>107hisserglnglythrphethrserasptyrserlystyrleuaspgly151015glnalaalaglnaspphevalglntrpleumetasnglyglyglygly202530glyserglyglyglyglyserglyglyglyglyseralagluserlys354045tyrglyproprocysproprocysproalaproglupheleuglygly505560proservalpheleupheproprolysprolysaspthrleumetile65707580serargthrprogluvalthrcysvalvalvalaspvalserglnglu859095aspprogluvalglnpheasntrptyrvalaspglyvalgluvalhis100105110asnalalysthrlysproargglugluglnphealaserthrtyrarg115120125valvalservalleuthrvalleuhisglnasptrpleuasnglylys130135140glutyrlyscyslysvalserasnlysglyleuproserserileglu145150155160lysthrileserlysalalysglyglnproarggluproglnvaltyr165170175thrleuproproserglngluglumetthrlysasnglnvalserleu180185190thrcysleuvallysglyphetyrproseraspilealavalglutrp195200205gluserasnglyglnprogluasnasntyrlysthrthrproproval210215220leuaspseraspglyserphepheleutyrserargleuthrvalasp225230235240lysserargtrpglngluglyasnvalphesercysservalmethis245250255glualaleuhisasnhistyrthrglnlysserleuserleuserleu260265270gly<210>108<211>283<212>prt<213>人工序列(artificialsequence)<400>108hisserglnglythrphethrserasptyrserlystyrleuaspgly151015glnalaalaglnaspphevalglntrpleumetasnglyglyproser202530serglyalaproproproserglyglyglyglyserglyglyglygly354045serglyglyglyglyseralagluserlystyrglyproprocyspro505560procysproalaproglupheleuglyglyproservalpheleuphe65707580proprolysprolysaspthrleumetileserargthrprogluval859095thrcysvalvalvalaspvalserglngluaspprogluvalglnphe100105110asntrptyrvalaspglyvalgluvalhisasnalalysthrlyspro115120125argglugluglnphealaserthrtyrargvalvalservalleuthr130135140valleuhisglnasptrpleuasnglylysglutyrlyscyslysval145150155160serasnlysglyleuproserserileglulysthrileserlysala165170175lysglyglnproarggluproglnvaltyrthrleuproprosergln180185190gluglumetthrlysasnglnvalserleuthrcysleuvallysgly195200205phetyrproseraspilealavalglutrpgluserasnglyglnpro210215220gluasnasntyrlysthrthrproprovalleuaspseraspglyser225230235240phepheleutyrserargleuthrvalasplysserargtrpglnglu245250255glyasnvalphesercysservalmethisglualaleuhisasnhis260265270tyrthrglnlysserleuserleuserleugly275280<210>109<211>273<212>prt<213>人工序列(artificialsequence)<400>109hisserglnglythrphethrserasptyrserlystyrleuaspser151015glnalaalaglnaspphevalglntrpleumetasnthrglyglygly202530glyserglyglyglyglyserglyglyglyglyseralagluserlys354045tyrglyproprocysproprocysproalaproglupheleuglygly505560proservalpheleupheproprolysprolysaspthrleumetile65707580serargthrprogluvalthrcysvalvalvalaspvalserglnglu859095aspprogluvalglnpheasntrptyrvalaspglyvalgluvalhis100105110asnalalysthrlysproargglugluglnphealaserthrtyrarg115120125valvalservalleuthrvalleuhisglnasptrpleuasnglylys130135140glutyrlyscyslysvalserasnlysglyleuproserserileglu145150155160lysthrileserlysalalysglyglnproarggluproglnvaltyr165170175thrleuproproserglngluglumetthrlysasnglnvalserleu180185190thrcysleuvallysglyphetyrproseraspilealavalglutrp195200205gluserasnglyglnprogluasnasntyrlysthrthrproproval210215220leuaspseraspglyserphepheleutyrserargleuthrvalasp225230235240lysserargtrpglngluglyasnvalphesercysservalmethis245250255glualaleuhisasnhistyrthrglnlysserleuserleuserleu260265270gly<210>110<211>283<212>prt<213>人工序列(artificialsequence)<400>110hisserglnglythrphethrserasptyrserlystyrleuaspser151015glnalaalaglnaspphevalglntrpleumetasnthrglyproser202530serglyalaproproproserglyglyglyglyserglyglyglygly354045serglyglyglyglyseralagluserlystyrglyproprocyspro505560procysproalaproglupheleuglyglyproservalpheleuphe65707580proprolysprolysaspthrleumetileserargthrprogluval859095thrcysvalvalvalaspvalserglngluaspprogluvalglnphe100105110asntrptyrvalaspglyvalgluvalhisasnalalysthrlyspro115120125argglugluglnphealaserthrtyrargvalvalservalleuthr130135140valleuhisglnasptrpleuasnglylysglutyrlyscyslysval145150155160serasnlysglyleuproserserileglulysthrileserlysala165170175lysglyglnproarggluproglnvaltyrthrleuproprosergln180185190gluglumetthrlysasnglnvalserleuthrcysleuvallysgly195200205phetyrproseraspilealavalglutrpgluserasnglyglnpro210215220gluasnasntyrlysthrthrproprovalleuaspseraspglyser225230235240phepheleutyrserargleuthrvalasplysserargtrpglnglu245250255glyasnvalphesercysservalmethisglualaleuhisasnhis260265270tyrthrglnlysserleuserleuserleugly275280<210>111<211>273<212>prt<213>人工序列(artificialsequence)<400>111hisserglnglythrphethrserasptyrserlystyrleuaspglu151015glualaalaglnaspphevalglntrpleumetasnthrglyglygly202530glyserglyglyglyglyserglyglyglyglyseralagluserlys354045tyrglyproprocysproprocysproalaproglupheleuglygly505560proservalpheleupheproprolysprolysaspthrleumetile65707580serargthrprogluvalthrcysvalvalvalaspvalserglnglu859095aspprogluvalglnpheasntrptyrvalaspglyvalgluvalhis100105110asnalalysthrlysproargglugluglnphealaserthrtyrarg115120125valvalservalleuthrvalleuhisglnasptrpleuasnglylys130135140glutyrlyscyslysvalserasnlysglyleuproserserileglu145150155160lysthrileserlysalalysglyglnproarggluproglnvaltyr165170175thrleuproproserglngluglumetthrlysasnglnvalserleu180185190thrcysleuvallysglyphetyrproseraspilealavalglutrp195200205gluserasnglyglnprogluasnasntyrlysthrthrproproval210215220leuaspseraspglyserphepheleutyrserargleuthrvalasp225230235240lysserargtrpglngluglyasnvalphesercysservalmethis245250255glualaleuhisasnhistyrthrglnlysserleuserleuserleu260265270gly<210>112<211>283<212>prt<213>人工序列(artificialsequence)<400>112hisserglnglythrphethrserasptyrserlystyrleuaspglu151015glualaalaglnaspphevalglntrpleumetasnthrglyproser202530serglyalaproproproserglyglyglyglyserglyglyglygly354045serglyglyglyglyseralagluserlystyrglyproprocyspro505560procysproalaproglupheleuglyglyproservalpheleuphe65707580proprolysprolysaspthrleumetileserargthrprogluval859095thrcysvalvalvalaspvalserglngluaspprogluvalglnphe100105110asntrptyrvalaspglyvalgluvalhisasnalalysthrlyspro115120125argglugluglnphealaserthrtyrargvalvalservalleuthr130135140valleuhisglnasptrpleuasnglylysglutyrlyscyslysval145150155160serasnlysglyleuproserserileglulysthrileserlysala165170175lysglyglnproarggluproglnvaltyrthrleuproprosergln180185190gluglumetthrlysasnglnvalserleuthrcysleuvallysgly195200205phetyrproseraspilealavalglutrpgluserasnglyglnpro210215220gluasnasntyrlysthrthrproprovalleuaspseraspglyser225230235240phepheleutyrserargleuthrvalasplysserargtrpglnglu245250255glyasnvalphesercysservalmethisglualaleuhisasnhis260265270tyrthrglnlysserleuserleuserleugly275280<210>113<211>273<212>prt<213>人工序列(artificialsequence)<400>113hisserglnglythrphethrserasptyrserlystyrleuaspglu151015glualaalaglnaspphevalglntrpleumetasnglyglyglygly202530glyserglyglyglyglyserglyglyglyglyseralagluserlys354045tyrglyproprocysproprocysproalaproglupheleuglygly505560proservalpheleupheproprolysprolysaspthrleumetile65707580serargthrprogluvalthrcysvalvalvalaspvalserglnglu859095aspprogluvalglnpheasntrptyrvalaspglyvalgluvalhis100105110asnalalysthrlysproargglugluglnphealaserthrtyrarg115120125valvalservalleuthrvalleuhisglnasptrpleuasnglylys130135140glutyrlyscyslysvalserasnlysglyleuproserserileglu145150155160lysthrileserlysalalysglyglnproarggluproglnvaltyr165170175thrleuproproserglngluglumetthrlysasnglnvalserleu180185190thrcysleuvallysglyphetyrproseraspilealavalglutrp195200205gluserasnglyglnprogluasnasntyrlysthrthrproproval210215220leuaspseraspglyserphepheleutyrserargleuthrvalasp225230235240lysserargtrpglngluglyasnvalphesercysservalmethis245250255glualaleuhisasnhistyrthrglnlysserleuserleuserleu260265270gly<210>114<211>283<212>prt<213>人工序列(artificialsequence)<400>114hisserglnglythrphethrserasptyrserlystyrleuaspglu151015glualaalaglnaspphevalglntrpleumetasnglyglyproser202530serglyalaproproproserglyglyglyglyserglyglyglygly354045serglyglyglyglyseralagluserlystyrglyproprocyspro505560procysproalaproglupheleuglyglyproservalpheleuphe65707580proprolysprolysaspthrleumetileserargthrprogluval859095thrcysvalvalvalaspvalserglngluaspprogluvalglnphe100105110asntrptyrvalaspglyvalgluvalhisasnalalysthrlyspro115120125argglugluglnphealaserthrtyrargvalvalservalleuthr130135140valleuhisglnasptrpleuasnglylysglutyrlyscyslysval145150155160serasnlysglyleuproserserileglulysthrileserlysala165170175lysglyglnproarggluproglnvaltyrthrleuproprosergln180185190gluglumetthrlysasnglnvalserleuthrcysleuvallysgly195200205phetyrproseraspilealavalglutrpgluserasnglyglnpro210215220gluasnasntyrlysthrthrproprovalleuaspseraspglyser225230235240phepheleutyrserargleuthrvalasplysserargtrpglnglu245250255glyasnvalphesercysservalmethisglualaleuhisasnhis260265270tyrthrglnlysserleuserleuserleugly275280<210>115<211>283<212>prt<213>人工序列(artificialsequence)<400>115hisserglnglythrphethrserasptyrserlystyrleuaspglu151015argalaalaglnaspphevalglntrpleumetasnglyglyproser202530serglyalaproproproserglyglyglyglyalaglyglyglygly354045alaglyglyglyglyalaalagluserlystyrglyproprocyspro505560procysproalaproglupheleuglyglyproservalpheleuphe65707580proprolysprolysaspthrleumetileserargthrprogluval859095thrcysvalvalvalaspvalserglngluaspprogluvalglnphe100105110asntrptyrvalaspglyvalgluvalhisasnalalysthrlyspro115120125argglugluglnphealaserthrtyrargvalvalservalleuthr130135140valleuhisglnasptrpleuasnglylysglutyrlyscyslysval145150155160serasnlysglyleuproserserileglulysthrileserlysala165170175lysglyglnproarggluproglnvaltyrthrleuproprosergln180185190gluglumetthrlysasnglnvalserleuthrcysleuvallysgly195200205phetyrproseraspilealavalglutrpgluserasnglyglnpro210215220gluasnasntyrlysthrthrproprovalleuaspseraspglyser225230235240phepheleutyrserargleuthrvalasplysserargtrpglnglu245250255glyasnvalphesercysservalmethisglualaleuhisasnhis260265270tyrthrglnlysserleuserleuserleugly275280<210>116<211>280<212>prt<213>人工序列(artificialsequence)<400>116hisserglnglythrphethrserasptyrserlystyrleuaspglu151015glnalaalaglnaspphevalglntrpleumetasnthrglyproser202530serglyalaproproproserglyglyglyglyalaglyglyglygly354045alaglyglyglyglyalaasplysthrhisthrcysproprocyspro505560alaprogluleuleuglyglyproservalpheleupheproprolys65707580prolysaspthrleumetileserargthrprogluvalthrcysval859095valvalaspvalserhisgluaspprogluvallyspheasntrptyr100105110valaspglyvalgluvalhisasnalalysthrlysproarggluglu115120125glntyrglyserthrtyrargvalvalservalleuthrvalleuhis130135140glnasptrpleuasnglylysglutyrlyscyslysvalserasnlys145150155160alaleuproalaproileglulysthrileserlysalalysglygln165170175proarggluproglnvaltyrthrleuproproserargaspgluleu180185190thrlysasnglnvalserleuthrcysleuvallysglyphetyrpro195200205seraspilealavalglutrpgluserasnglyglnprogluasnasn210215220tyrlysthrthrproprovalleuaspseraspglyserphepheleu225230235240tyrserlysleuthrvalasplysserargtrpglnglnglyasnval245250255phesercysservalmethisglualaleuhisasnhistyrthrgln260265270lysserleuserleuserprogly275280<210>117<211>280<212>prt<213>人工序列(artificialsequence)<400>117hisserglnglythrphethrserasptyrserlystyrleuaspgly151015glnalaalaglnaspphevalglntrpleumetasnglyglyproser202530serglyalaproproproserglyglyglyglyalaglyglyglygly354045alaglyglyglyglyalaasplysthrhisthrcysproprocyspro505560alaprogluleuleuglyglyproservalpheleupheproprolys65707580prolysaspthrleumetileserargthrprogluvalthrcysval859095valvalaspvalserhisgluaspprogluvallyspheasntrptyr100105110valaspglyvalgluvalhisasnalalysthrlysproarggluglu115120125glntyrglyserthrtyrargvalvalservalleuthrvalleuhis130135140glnasptrpleuasnglylysglutyrlyscyslysvalserasnlys145150155160alaleuproalaproileglulysthrileserlysalalysglygln165170175proarggluproglnvaltyrthrleuproproserargaspgluleu180185190thrlysasnglnvalserleuthrcysleuvallysglyphetyrpro195200205seraspilealavalglutrpgluserasnglyglnprogluasnasn210215220tyrlysthrthrproprovalleuaspseraspglyserphepheleu225230235240tyrserlysleuthrvalasplysserargtrpglnglnglyasnval245250255phesercysservalmethisglualaleuhisasnhistyrthrgln260265270lysserleuserleuserprogly275280<210>118<211>280<212>prt<213>人工序列(artificialsequence)<400>118hisserglnglythrphethrserasptyrserlystyrleuaspglu151015glnalaalaglnaspphevalglntrpleumetasnglyproserser202530glyalaproproproserglyglyglyglyserglyglyglyglyser354045glyglyglyglyseralaasplysthrhisthrcysproprocyspro505560alaprogluleuleuglyglyproservalpheleupheproprolys65707580prolysaspthrleumetileserargthrprogluvalthrcysval859095valvalaspvalserhisgluaspprogluvallyspheasntrptyr100105110valaspglyvalgluvalhisasnalalysthrlysproarggluglu115120125glntyrglyserthrtyrargvalvalservalleuthrvalleuhis130135140glnasptrpleuasnglylysglutyrlyscyslysvalserasnlys145150155160alaleuproalaproileglulysthrileserlysalalysglygln165170175proarggluproglnvaltyrthrleuproproserargaspgluleu180185190thrlysasnglnvalserleuthrcysleuvallysglyphetyrpro195200205seraspilealavalglutrpgluserasnglyglnprogluasnasn210215220tyrlysthrthrproprovalleuaspseraspglyserphepheleu225230235240tyrserlysleuthrvalasplysserargtrpglnglnglyasnval245250255phesercysservalmethisglualaleuhisasnhistyrthrgln260265270lysserleuserleuserprogly275280<210>119<211>282<212>prt<213>人工序列(artificialsequence)<400>119hisserglnglythrphethrserasptyrserlystyrleuaspglu151015argalaalaglnaspphevalglntrpleumetasnthrglyproser202530serglyalaproproproserglyglyglyglyalaglyglyglygly354045alaglyglyglyglyalagluserlystyrglyproprocyspropro505560cysproalaproglualaalaglyglyproservalpheleuphepro65707580prolysprolysaspthrleumetileserargthrprogluvalthr859095cysvalvalvalaspvalserglngluaspprogluvalglnpheasn100105110trptyrvalaspglyvalgluvalhisasnalalysthrlysproarg115120125glugluglnphealaserthrtyrargvalvalservalleuthrval130135140leuhisglnasptrpleuasnglylysglutyrlyscyslysvalser145150155160asnlysglyleuproserserileglulysthrileserlysalalys165170175glyglnproarggluproglnvaltyrthrleuproproserglnglu180185190glumetthrlysasnglnvalserleuthrcysleuvallysglyphe195200205tyrproseraspilealavalglutrpgluserasnglyglnproglu210215220asnasntyrlysthrthrproprovalleuaspseraspglyserphe225230235240pheleutyrserargleuthrvalasplysserargtrpglnglugly245250255asnvalphesercysservalmethisglualaleuhisasnhistyr260265270thrglnlysserleuserleuserleugly275280<210>120<211>281<212>prt<213>人工序列(artificialsequence)<400>120hisserglnglythrphethrserasptyrserlystyrleuaspglu151015gluargalaglnaspphevalglntrpleumetasnthrglyproser202530serglyalaproproproserglyglyglyglyserglyglyglygly354045serglyglyglyglyseralaasplysthrhisthrcysproprocys505560proalaprogluleuleuglyglyproservalpheleuphepropro65707580lysprolysaspthrleumetileserargthrprogluvalthrcys859095valvalvalaspvalserhisgluaspprogluvallyspheasntrp100105110tyrvalaspglyvalgluvalhisasnalalysthrlysproargglu115120125gluglntyrglyserthrtyrargvalvalservalleuthrvalleu130135140hisglnasptrpleuasnglylysglutyrlyscyslysvalserasn145150155160lysalaleuproalaproileglulysthrileserlysalalysgly165170175glnproarggluproglnvaltyrthrleuproproserargaspglu180185190leuthrlysasnglnvalserleuthrcysleuvallysglyphetyr195200205proseraspilealavalglutrpgluserasnglyglnprogluasn210215220asntyrlysthrthrproprovalleuaspseraspglyserphephe225230235240leutyrserlysleuthrvalasplysserargtrpglnglnglyasn245250255valphesercysservalmethisglualaleuhisasnhistyrthr260265270glnlysserleuserleuserprogly275280<210>121<211>280<212>prt<213>人工序列(artificialsequence)<400>121hisserglnglythrphethrserasptyrserlystyrleuaspser151015glnargalaglnaspphevalglntrpleumetasnthrglyproser202530serglyalaproproproserglyglyglyglyserglyglyglygly354045serglyglyglyglyserasplysthrhisthrcysproprocyspro505560alaprogluleuleuglyglyproservalpheleupheproprolys65707580prolysaspthrleumetileserargthrprogluvalthrcysval859095valvalaspvalserhisgluaspprogluvallyspheasntrptyr100105110valaspglyvalgluvalhisasnalalysthrlysproarggluglu115120125glntyrglyserthrtyrargvalvalservalleuthrvalleuhis130135140glnasptrpleuasnglylysglutyrlyscyslysvalserasnlys145150155160alaleuproalaproileglulysthrileserlysalalysglygln165170175proarggluproglnvaltyrthrleuproproserargaspgluleu180185190thrlysasnglnvalserleuthrcysleuvallysglyphetyrpro195200205seraspilealavalglutrpgluserasnglyglnprogluasnasn210215220tyrlysthrthrproprovalleuaspseraspglyserphepheleu225230235240tyrserlysleuthrvalasplysserargtrpglnglnglyasnval245250255phesercysservalmethisglualaleuhisasnhistyrthrgln260265270lysserleuserleuserprogly275280<210>122<211>281<212>prt<213>人工序列(artificialsequence)<400>122hisserglnglythrphethrseraspleuserlysglnmetaspser151015argalaalaglnasppheileglutrpleulysasnglyglyproser202530serglyalaproproproserglyglyglyglyalaglyglyglygly354045alaglyglyglyglyalaalaasplysthrhisthrcysproprocys505560proalaprogluleuleuglyglyproservalpheleuphepropro65707580lysprolysaspthrleumetileserargthrprogluvalthrcys859095valvalvalaspvalserhisgluaspprogluvallyspheasntrp100105110tyrvalaspglyvalgluvalhisasnalalysthrlysproargglu115120125gluglntyrglyserthrtyrargvalvalservalleuthrvalleu130135140hisglnasptrpleuasnglylysglutyrlyscyslysvalserasn145150155160lysalaleuproalaproileglulysthrileserlysalalysgly165170175glnproarggluproglnvaltyrthrleuproproserargaspglu180185190leuthrlysasnglnvalserleuthrcysleuvallysglyphetyr195200205proseraspilealavalglutrpgluserasnglyglnprogluasn210215220asntyrlysthrthrproprovalleuaspseraspglyserphephe225230235240leutyrserlysleuthrvalasplysserargtrpglnglnglyasn245250255valphesercysservalmethisglualaleuhisasnhistyrthr260265270glnlysserleuserleuserprogly275280<210>123<211>281<212>prt<213>人工序列(artificialsequence)<400>123hisserglnglythrphethrseraspleuserlysglnmetaspser151015argglualaglnasppheileglutrpleulysasnthrglyproser202530serglyalaproproproserglyglyglyglyserglyglyglygly354045serglyglyglyglyserasplysthrhisthrcysproprocyspro505560alaprogluleuleuglyglyproservalpheleupheproprolys65707580prolysaspthrleumetileserargthrprogluvalthrcysval859095valvalaspvalserhisgluaspprogluvallyspheasntrptyr100105110valaspglyvalgluvalhisasnalalysthrlysproarggluglu115120125glntyralaserthrtyrargvalvalservalleuthrvalleuhis130135140glnasptrpleuasnglylysglutyrlyscyslysvalserasnlys145150155160alaleuproalaproileglulysthrileserlysalalysglygln165170175proarggluproglnvaltyrthrleuproproserargaspgluleu180185190thrlysasnglnvalserleuthrcysleuvallysglyphetyrpro195200205seraspilealavalglutrpgluserasnglyglnprogluasnasn210215220tyrlysthrthrproprovalleuaspseraspglyserphepheleu225230235240tyrserlysleuthrvalasplysserargtrpglnglnglyasnval245250255phesercysservalmethisglualaleuhisasnhistyrthrgln260265270lysserleuserleuserproglylys275280<210>124<211>281<212>prt<213>人工序列(artificialsequence)<400>124hisserglnglythrphethrserasptyrserlystyrleuaspglu151015gluargalaglnaspphevalglntrpleumetasnthrglyproser202530serglyalaproproproserglyglyglyglyserglyglyglygly354045serglyglyglyglyseralaasplysthrhisthrcysproprocys505560proalaprogluleuleuglyglyproservalpheleuphepropro65707580lysprolysaspthrleumetileserargthrprogluvalthrcys859095valvalvalaspvalserhisgluaspprogluvallyspheasntrp100105110tyrvalaspglyvalgluvalhisasnalalysthrlysproargglu115120125gluglntyrglyserthrtyrargvalvalservalleuthrvalleu130135140hisglnasptrpleuasnglylysglutyrlyscyslysvalserasn145150155160lysalaleuproalaproileglulysthrileserlysalalysgly165170175glnproarggluproglnvaltyrthrleuproproserargaspglu180185190leuthrlysasnglnvalserleuthrcysleuvallysglyphetyr195200205proseraspilealavalglutrpgluserasnglyglnprogluasn210215220asntyrlysthrthrproprovalleuaspseraspglyserphephe225230235240leutyrserlysleuthrvalasplysserargtrpglnglnglyasn245250255valphesercysservalmethisglualaleuhisasnhistyrthr260265270glnlysserleuserleuserprogly275280<210>125<211>272<212>prt<213>人工序列(artificialsequence)<400>125hisserglnglythrphethrserasptyrserglutyrleuaspser151015gluargalaargaspphevalalatrpleuglualaglyglyglygly202530glyglyserglyglyglyglyserglyglyglyglyseralaasplys354045thrhisthrcysproprocysproalaprogluleuleuglyglypro505560servalpheleupheproprolysprolysaspthrleumetileser65707580argthrprogluvalthrcysvalvalvalaspvalserhisgluasp859095progluvallyspheasntrptyrvalaspglyvalgluvalhisasn100105110alalysthrlysproargglugluglntyrglyserthrtyrargval115120125valservalleuthrvalleuhisglnasptrpleuasnglylysglu130135140tyrlyscyslysvalserasnlysalaleuproalaproileglulys145150155160thrileserlysalalysglyglnproarggluproglnvaltyrthr165170175leuproproserargaspgluleuthrlysasnglnvalserleuthr180185190cysleuvallysglyphetyrproseraspilealavalglutrpglu195200205serasnglyglnprogluasnasntyrlysthrthrproprovalleu210215220aspseraspglyserphepheleutyrserlysleuthrvalasplys225230235240serargtrpglnglnglyasnvalphesercysservalmethisglu245250255alaleuhisasnhistyrthrglnlysserleuserleuserprogly260265270<210>126<211>277<212>prt<213>人工序列(artificialsequence)<400>126hisserglnglythrphethrserasptyrserlystyrleugluglu151015glualavalargleupheileglntrpleumetasnthrglysergly202530glyglyglyserglyglyglyglyserglyglyglyglyserglupro354045lyssercysasplysthrhisthrcysproprocysproalaproglu505560leuleuglyglyproservalpheleupheproprolysprolysasp65707580thrleumetileserargthrprogluvalthrcysvalvalvalasp859095valserhisgluaspprogluvallyspheasntrptyrvalaspgly100105110valgluvalhisasnalalysthrlysproargglugluglntyrala115120125serthrtyrargvalvalservalleuthrvalleuhisglnasptrp130135140leuasnglylysglutyrlyscyslysvalserasnlysalaleupro145150155160alaproileglulysthrileserlysalalysglyglnproargglu165170175proglnvaltyrthrleuproproserarggluglumetthrlysasn180185190glnvalserleuthrcysleuvallysglyphetyrproseraspile195200205alavalglutrpgluserasnglyglnprogluasnasntyrlysthr210215220thrproprovalleuaspseraspglyserphepheleutyrserlys225230235240leuthrvalasplysserargtrpglnglnglyasnvalphesercys245250255servalmethisglualaleuhisasnhistyrthrglnlysserleu260265270serleuserprogly275<210>127<211>277<212>prt<213>人工序列(artificialsequence)<400>127hisserglnglythrphethrserasptyrserlystyrleugluglu151015glualavalargleupheileglntrpleumetasnglyglyproser202530serglyalaproproproserglyglyserglyglyglyserglygly354045glyglyserasplysthrhisthrcysproprocysproalaproglu505560leuleuglyglyproservalpheleupheproprolysprolysasp65707580thrleumetileserargthrprogluvalthrcysvalvalvalasp859095valserhisgluaspprogluvallyspheasntrptyrvalaspgly100105110valgluvalhisasnalalysthrlysproargglugluglntyrgly115120125serthrtyrargvalvalservalleuthrvalleuhisglnasptrp130135140leuasnglylysglutyrlyscyslysvalserasnlysalaleupro145150155160alaproileglulysthrileserlysalalysglyglnproargglu165170175proglnvaltyrthrleuproproserargaspgluleuthrlysasn180185190glnvalserleuthrcysleuvallysglyphetyrproseraspile195200205alavalglutrpgluserasnglyglnprogluasnasntyrlysthr210215220thrproprovalleuaspseraspglyserphepheleutyrserlys225230235240leuthrvalasplysserargtrpglnglnglyasnvalphesercys245250255servalmethisglualaleuhisasnhistyrthrglnlysserleu260265270serleuserprogly275<210>128<211>289<212>prt<213>人工序列(artificialsequence)<400>128hisserglnglythrphethrserasptyrserlystyrleuaspglu151015glnalaalaglnaspphevalglntrpleumetasnthrlysargasn202530argasnasnilealaglyglyglyglyserglyglyglyglysergly354045glyglyglyserglyglyglyglyserglyglyglyglyseralaasp505560lysthrhisthrcysproprocysproalaprogluleuleuglygly65707580proservalpheleupheproprolysprolysaspthrleumetile859095serargthrprogluvalthrcysvalvalvalaspvalserhisglu100105110aspprogluvallyspheasntrptyrvalaspglyvalgluvalhis115120125asnalalysthrlysproargglugluglntyrglyserthrtyrarg130135140valvalservalleuthrvalleuhisglnasptrpleuasnglylys145150155160glutyrlyscyslysvalserasnlysalaleuproalaproileglu165170175lysthrileserlysalalysglyglnproarggluproglnvaltyr180185190thrleuproproserargaspgluleuthrlysasnglnvalserleu195200205thrcysleuvallysglyphetyrproseraspilealavalglutrp210215220gluserasnglyglnprogluasnasntyrlysthrthrproproval225230235240leuaspseraspglyserphepheleutyrserlysleuthrvalasp245250255lysserargtrpglnglnglyasnvalphesercysservalmethis260265270glualaleuhisasnhistyrthrglnlysserleuserleuserpro275280285gly<210>129<211>269<212>prt<213>人工序列(artificialsequence)<400>129hisserglnglythrphethrserasptyrserlysglnmetaspser151015glnargalaglnaspphevalglntrpleumetasnthrlysargasn202530argasnasnilealaglyglyglyglysergluarglyscyscysval354045glucysproprocysproalaproprovalalaglyproservalphe505560leupheproprolysprolysaspthrleumetileserargthrpro65707580gluvalthrcysvalvalvalaspvalserhisgluaspprogluval859095glnpheasntrptyrvalaspglyvalgluvalhisasnalalysthr100105110lysproargglugluglnpheasnserthrpheargvalvalserval115120125leuthrvalvalhisglnasptrpleuasnglylysglutyrlyscys130135140lysvalserasnlysglyleuproserserileglulysthrileser145150155160lysthrlysglyglnproarggluproglnvaltyrthrleupropro165170175serarggluglumetthrlysasnglnvalserleuthrcysleuval180185190lysglyphetyrproseraspilealavalglutrpgluserasngly195200205glnprogluasnasntyrlysthrthrproprometleuaspserasp210215220glyserphepheleutyrserlysleuthrvalasplysserargtrp225230235240glnglnglyasnvalphesercysservalmethisglualaleuhis245250255asnhistyrthrglnlysserleuserleuserprogly260265<210>130<211>281<212>prt<213>人工序列(artificialsequence)<400>130hisserglnglythrphethrserasptyrserlystyrleuaspgly151015glualaalaglnaspphevalglntrpleumetasnglyglyproser202530serglyalaproproproserglyglyglyglyalaglyglyglygly354045alaglyglyglyglyalaalaasplysthrhisthrcysproprocys505560proalaprogluleuleuglyglyproservalpheleuphepropro65707580lysprolysaspthrleumetileserargthrprogluvalthrcys859095valvalvalaspvalserhisgluaspprogluvallyspheasntrp100105110tyrvalaspglyvalgluvalhisasnalalysthrlysproargglu115120125gluglntyrglyserthrtyrargvalvalservalleuthrvalleu130135140hisglnasptrpleuasnglylysglutyrlyscyslysvalserasn145150155160lysalaleuproalaproileglulysthrileserlysalalysgly165170175glnproarggluproglnvaltyrthrleuproproserargaspglu180185190leuthrlysasnglnvalserleuthrcysleuvallysglyphetyr195200205proseraspilealavalglutrpgluserasnglyglnprogluasn210215220asntyrlysthrthrproprovalleuaspseraspglyserphephe225230235240leutyrserlysleuthrvalasplysserargtrpglnglnglyasn245250255valphesercysservalmethisglualaleuhisasnhistyrthr260265270glnlysserleuserleuserprogly275280<210>131<211>280<212>prt<213>人工序列(artificialsequence)<400>131hisserglnglythrphethrserasptyrserlystyrleuaspglu151015argalaalaglnaspphevalglntrpleuleuaspglyproserser202530glyalaproproproserglyglyserglyglyglyglyserglygly354045glyglyserglyglyalaasplysthrhisthrcysproprocyspro505560alaprogluleuleuglyglyproservalpheleupheproprolys65707580prolysaspthrleumetileserargthrprogluvalthrcysval859095valvalaspvalserhisgluaspprogluvallyspheasntrptyr100105110valaspglyvalgluvalhisasnalalysthrlysproarggluglu115120125glntyrglyserthrtyrargvalvalservalleuthrvalleuhis130135140glnasptrpleuasnglylysglutyrlyscyslysvalserasnlys145150155160alaleuproalaproileglulysthrileserlysalalysglygln165170175proarggluproglnvaltyrthrleuproproserargaspgluleu180185190thrlysasnglnvalserleuthrcysleuvallysglyphetyrpro195200205seraspilealavalglutrpgluserasnglyglnprogluasnasn210215220tyrlysthrthrproprovalleuaspseraspglyserphepheleu225230235240tyrserlysleuthrvalasplysserargtrpglnglnglyasnval245250255phesercysservalmethisglualaleuhisasnhistyrthrgln260265270lysserleuserleuserprogly275280<210>132<211>283<212>prt<213>人工序列(artificialsequence)<400>132hisserglnglythrphethrserasptyrserlystyrleuaspser151015glualaalaglnaspphevalglntrpleumetasnglyglyproser202530serglyalaproproproserglyglyglyglyserglyglyglygly354045serglyglyglyglyseralagluserlystyrglyproprocyspro505560procysproalaproglupheleuglyglyproservalpheleuphe65707580proprolysprolysaspthrleumetileserargthrprogluval859095thrcysvalvalvalaspvalserglngluaspprogluvalglnphe100105110asntrptyrvalaspglyvalgluvalhisasnalalysthrlyspro115120125argglugluglnphealaserthrtyrargvalvalservalleuthr130135140valleuhisglnasptrpleuasnglylysglutyrlyscyslysval145150155160serasnlysglyleuproserserileglulysthrileserlysala165170175lysglyglnproarggluproglnvaltyrthrleuproprosergln180185190gluglumetthrlysasnglnvalserleuthrcysleuvallysgly195200205phetyrproseraspilealavalglutrpgluserasnglyglnpro210215220gluasnasntyrlysthrthrproprovalleuaspseraspglyser225230235240phepheleutyrserargleuthrvalasplysserargtrpglnglu245250255glyasnvalphesercysservalmethisglualaleuhisasnhis260265270tyrthrglnlysserleuserleuserleugly275280<210>133<211>283<212>prt<213>人工序列(artificialsequence)<400>133hisserglnglythrphethrserasptyrserlysglnmetaspser151015glnargalaglnaspphevalglntrpleumetasnglyglyproser202530serglyalaproproproserglyglyglyglyalaglyglyglygly354045alaglyglyglyglyalaalagluserlystyrglyproprocyspro505560procysproalaproglualaalaglyglyproservalpheleuphe65707580proprolysprolysaspthrleumetileserargthrprogluval859095thrcysvalvalvalaspvalserglngluaspprogluvalglnphe100105110asntrptyrvalaspglyvalgluvalhisasnalalysthrlyspro115120125argglugluglnphealaserthrtyrargvalvalservalleuthr130135140valleuhisglnasptrpleuasnglylysglutyrlyscyslysval145150155160serasnlysglyleuproserserileglulysthrileserlysala165170175lysglyglnproarggluproglnvaltyrthrleuproprosergln180185190gluglumetthrlysasnglnvalserleuthrcysleuvallysgly195200205phetyrproseraspilealavalglutrpgluserasnglyglnpro210215220gluasnasntyrlysthrthrproprovalleuaspseraspglyser225230235240phepheleutyrserargleuthrvalasplysserargtrpglnglu245250255glyasnvalphesercysservalmethisglualaleuhisasnhis260265270tyrthrglnlysserleuserleuserleugly275280<210>134<211>40<212>prt<213>人工序列(artificialsequence)<400>134hisaspserglnglythrphethrserasptyrserlystyrleuasp151015serglnalaalaglnaspphevalglntrpleumetasnglyglypro202530serserglyalaproproproser3540<210>135<211>39<212>prt<213>人工序列(artificialsequence)<400>135hisxaaglnglythrphethrserasptyrserlystyrleuaspser151015glnalaalaglnaspphevalglntrpleumetasnglyglyproser202530serglyalaproproproser35<210>136<211>181<212>prt<213>人工序列(artificialsequence)<400>136hisproileproaspserserproleuleuglnpheglyglyglnval151015argglnargtyrleutyrthraspaspalaglnglnthrglualahis202530leugluilearggluaspglythrvalglyglyalaalaaspglnser354045progluserleuleuglnleulysalaleulysproglyvalilegln505560ileleuglyvallysthrserargpheleucysglnargproaspgly65707580alaleutyrglyserleuhispheaspproglualacysserphearg859095gluleuleuleugluaspglytyrasnvaltyrglnserglualahis100105110glyleuproleuhisleuproglyasnlysserprohisargasppro115120125alaproargglyproalaargpheleuproleuproglyleupropro130135140alaleuprogluproproglyileleualaproglnproproaspval145150155160glyserseraspproleusermetvalglyproserglnglyargser165170175prosertyralaser180<210>137<211>181<212>prt<213>人工序列(artificialsequence)<400>137hisproileproaspserserproleuleuglnpheglyglyglnval151015argglnargtyrleutyrthraspaspalaglnglnthrglualahis202530leugluilearggluaspglythrvalglyglyalaalaaspglnser354045progluserleuleuglnleulysalaleulysproglyvalilegln505560ileleuglyvallysthrserargpheleucysglnargproaspgly65707580alaleutyrglyserleuhispheaspproglualacysserphearg859095gluargleuleugluaspglytyrasnvaltyrglnserglualahis100105110glyleuproleuhisleuproglyasnlysserprohisargasppro115120125alaproargglyproalaargpheleuproleuproglyleupropro130135140alaleuprogluproproglyileleualaproglnproproaspval145150155160glyserseraspproleusermetvalglyglyserglnglyargser165170175prosertyrgluser180<210>138<211>181<212>prt<213>人工序列(artificialsequence)<400>138hisproileproaspserserproleuleuglnpheglyglyglnval151015argglnargtyrleutyrthraspaspalaglnglnthrglualahis202530leugluilearggluaspglythrvalglyglyalaalaaspglnser354045progluserleuleuglnleulysalaleulysproglyvalilegln505560ileleuglyvallysthrserargpheleucysglnargproaspgly65707580alaleutyrglyserleuhispheaspproglualacysserphearg859095gluargleuleugluaspglytyrasnvaltyrglnserglualahis100105110glyleuproleuhiscysproglyasnlysserprohisargasppro115120125alaproargglyprocysargpheleuproleuproglyleupropro130135140alaleuprogluproproglyileleualaproglnproproaspval145150155160glyserseraspproleusermetvalglyglyserglnglyargser165170175prosertyrgluser180<210>139<211>177<212>prt<213>人工序列(artificialsequence)<400>139aspserserproleuleuglnpheglyglyglnvalargglnargtyr151015leutyrthraspaspalaglnglnthrglualahisleugluilearg202530gluaspglythrvalglyglyalaalaaspglnserprogluserleu354045leuglnleulysalaleulysproglyvalileglnileleuglyval505560lysthrserargpheleucysglnargproaspglyalaleutyrgly65707580serleuhispheaspproglualacysserphearggluleuleuleu859095gluaspglytyrasnvaltyrglnserglualahisglyleuproleu100105110hiscysproglyasnlysserprohisargaspproalaproarggly115120125procysargpheleuproleuproglyleuproproalaleuproglu130135140proproglyileleualaproglnproproaspvalglyserserasp145150155160proleualametvalglyproserglnglyargserprosertyrala165170175ser<210>140<211>181<212>prt<213>人工序列(artificialsequence)<400>140hisproileproaspserserproleuleuglnpheglyglyglnval151015argglnargtyrleutyrthraspaspalaglnglnthrglualahis202530leugluilearggluaspglythrvalglyglyalaalaaspglnser354045progluserleuleuglnleulysalaleulysproglyvalilegln505560ileleuglyvallysthrserargpheleucysglnargproaspgly65707580alaleutyrglyserleuhispheaspproglualacysserphearg859095gluargleuleugluaspglytyrasnvaltyrglnserglualahis100105110glyleuproleuhiscysproglyasnlysserprohisargasppro115120125alaproargglyprocysargpheleuproleuproglyleupropro130135140alaleuprogluproproglyileleualaproglnproproaspval145150155160glyserseraspproleualametvalglyglyserglnglyargser165170175prosertyrgluser180<210>141<211>181<212>prt<213>人工序列(artificialsequence)<400>141hisproileproaspserserproleuleuglnpheglyglyglnval151015argglnargtyrleutyrthraspaspalaglnglnthrglualahis202530leugluilearggluaspglythrvalglyglyalagluaspglnser354045progluserleuleuglnleulysalaleulysproglyvalilegln505560ileleuglyvallysthrserargpheleucysglnargproaspgly65707580alaleutyrglyserleuhispheaspproglualacysserphearg859095gluargleuleugluaspglytyrasnvaltyrglnserglualahis100105110glyleuproleuhiscysproglyasnlysserprohisargasppro115120125alaproargglyprocysargpheleuproleuproglyleupropro130135140alaleuprogluproproglyileleualaproglnproproaspval145150155160glyserseraspproleusermetvalglyglyserglnglyargser165170175prosertyrgluser180<210>142<211>181<212>prt<213>人工序列(artificialsequence)<400>142hisproileproaspserserproleuleuglnpheglyglyglnval151015argglnargtyrleutyrthraspaspalaglnglnthrglualahis202530leugluilearggluaspglythrvalglyglyalaalaaspglnser354045progluserleuleuglnleulysalaleulysproglyvalilegln505560ileleuglyvallysthrserargpheleucysglnargproaspgly65707580alaleutyrglyserleuhispheaspproglualacysserphearg859095gluargleuleugluaspglytyrasnvaltyrglnserglualahis100105110glyleuproleuhiscysproglyasnlysserprohisargasppro115120125alaproargglyprocysargpheleuproleuproglyleupropro130135140alaleuprogluproproglyileleualaproglnproproaspval145150155160glyserseraspproleusermetvalgluproserglnglyargser165170175prosertyralaser180<210>143<211>181<212>prt<213>人工序列(artificialsequence)<400>143hisproileproasps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erargtrpglnglnglyasn245250255valphesercysservalmethisglualaleuhisasnhistyrthr260265270glnlysserleuserleuserproglyglyglyglyglyalaglygly275280285glyglyalaglyglyglyglyalahisproileproaspserserpro290295300leuleuglnpheglyglyglnvalargglnargtyrleutyrthrasp305310315320aspalaglnglnthrglualahisleugluilearggluaspglythr325330335valglyglyalaalaaspglnserprogluserleuleuglnleulys340345350alaleulysproglyvalileglnileleuglyvallysthrserarg355360365pheleucysglnargproaspglyalaleutyrglyserleuhisphe370375380aspproglualacysserphearggluleuleuleugluaspglytyr385390395400asnvaltyrglnserglualahisglyleuproleuhisleuprogly405410415asnlysserprohisargaspproalaproargglyproalaargphe420425430leuproleuproglyleuproproalaleuprogluproproglyile435440445leualaproglnproproaspvalglyserseraspproleusermet450455460valglyproserglnglyargserprosertyralaser465470475<210>150<211>480<212>prt<213>人工序列(artificialsequence)<400>150hisserglnglythrphethrserasptyrserlystyrleuaspglu151015argalaalaglnaspphevalglntrpleumetasnglyglyproser202530serglyalaproproproserglyglyglyglyalaglyglyglygly354045alaglyglyglyglyalaalagluserlystyrglyproprocyspro505560procysproalaproglupheleuglyglyproservalpheleuphe65707580proprolysprolysaspthrleumetileserargthrprogluval859095thrcysvalvalvalaspvalserglngluaspprogluvalglnphe100105110asntrptyrvalaspglyvalgluvalhisasnalalysthrlyspro115120125argglugluglnphealaserthrtyrargvalvalservalleuthr130135140valleuhisglnasptrpleuasnglylysglutyrlyscyslysval145150155160serasnlysglyleuproserserileglulysthrileserlysala165170175lysglyglnproarggluproglnvaltyrthrleuproprosergln180185190gluglumetthrlysasnglnvalserleuthrcysleuvallysgly195200205phetyrproseraspilealavalglutrpgluserasnglyglnpro210215220gluasnasntyrlysthrthrproprovalleuaspseraspglyser225230235240phepheleutyrserargleuthrvalasplysserargtrpglnglu245250255glyasnvalphesercysservalmethisglualaleuhisasnhis260265270tyrthrglnlysserleuserleuserleuglyglyglyglyglyala275280285glyglyglyglyalaglyglyglyglyalaalahisproileproasp290295300serserproleuleuglnpheglyglyglnvalargglnargtyrleu305310315320tyrthraspaspalaglnglnthrglualahisleugluileargglu325330335aspglythrvalglyglyalaalaaspglnserprogluserleuleu340345350glnleulysalaleulysproglyvalileglnileleuglyvallys355360365thrserargpheleucysglnargproaspglyalaleutyrglyser370375380leuhispheaspproglualacysserphearggluargleuleuglu385390395400aspglytyrasnvaltyrglnserglualahisglyleuproleuhis405410415leuproglyasnlysserprohisargaspproalaproargglypro420425430alaargpheleuproleuproglyleuproproalaleuproglupro435440445proglyileleualaproglnproproaspvalglyserserasppro450455460leusermetvalglyglyserglnglyargserprosertyrgluser465470475480<210>151<211>480<212>prt<213>人工序列(artificialsequence)<400>151hisserglnglythrphethrserasptyrserlystyrleuaspglu151015argalaalaglnaspphevalglntrpleumetasnglyglyproser202530serglyalaproproproserglyglyglyglyserglyglyglygly354045serglyglyglyglysergluserlystyrglyproprocyspropro505560cysproalaproglupheleuglyglyproservalpheleuphepro65707580prolysprolysaspthrleumetileserargthrprogluvalthr859095cysvalvalvalaspvalserglngluaspprogluvalglnpheasn100105110trptyrvalaspglyvalgluvalhisasnalalysthrlysproarg115120125glugluglnphealaserthrtyrargvalvalservalleuthrval130135140leuhisglnasptrpleuasnglylysglutyrlyscyslysvalser145150155160asnlysglyleuproserserileglulysthrileserlysalalys165170175glyglnproarggluproglnvaltyrthrleuproproserglnglu180185190glumetthrlysasnglnvalserleuthrcysleuvallysglyphe195200205tyrproseraspilealavalglutrpgluserasnglyglnproglu210215220asnasntyrlysthrthrproprovalleuaspseraspglyserphe225230235240pheleutyrserargleuthrvalasplysserargtrpglnglugly245250255asnvalphesercysservalmethisglualaleuhisasnhistyr260265270thrglnlysserleuserleuserleuglylysglyglyglyglyser275280285glyglyglyglyserglyglyglyglyseralahisproileproasp290295300serserproleuleuglnpheglyglyglnvalargglnargtyrleu305310315320tyrthraspaspalaglnglnthrglualahisleugluileargglu325330335aspglythrvalglyglyalaalaaspglnserprogluserleuleu340345350glnleulysalaleulysproglyvalileglnileleuglyvallys355360365thrserargpheleucysglnargproaspglyalaleutyrglyser370375380leuhispheaspproglualacysserphearggluargleuleuglu385390395400aspglytyrasnvaltyrglnserglualahisglyleuproleuhis405410415cysproglyasnlysserprohisargaspproalaproargglypro420425430cysargpheleuproleuproglyleuproproalaleuproglupro435440445proglyileleualaproglnproproaspvalglyserserasppro450455460leusermetvalglyglyserglnglyargserprosertyrgluser465470475480<210>152<211>477<212>prt<213>人工序列(artificialsequence)<400>152hisserglnglythrphethrserasptyrserlystyrleuaspglu151015argalaalaglnaspphevalglntrpleumetasnglyglyproser202530serglyalaproproproserglyglyglyglyserglyglyglygly354045serglyglyglyglyseralaasplysthrhisthrcysproprocys505560proalaprogluleuleuglyglyproservalpheleuphepropro65707580lysprolysaspthrleumetileserargthrprogluvalthrcys859095valvalvalaspvalserhisgluaspprogluvallyspheasntrp100105110tyrvalaspglyvalgluvalhisasnalalysthrlysproargglu115120125gluglntyrglyserthrtyrargvalvalservalleuthrvalleu130135140hisglnasptrpleuasnglylysglutyrlyscyslysvalserasn145150155160lysalaleuproalapro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phethrserasptyrserlystyrleuaspglu151015glnalaalaglnaspphevalglntrpleumetasnthrglyproser202530serglyalaproproproserglyglyglyglyalaglyglyglygly354045alaglyglyglyglyalaasplysthrhisthrcysproprocyspro505560alaprogluleuleuglyglyproservalpheleupheproprolys65707580prolysaspthrleumetileserargthrprogluvalthrcysval859095valvalaspvalserhisgluaspprogluvallyspheasntrptyr100105110valaspglyvalgluvalhisasnalalysthrlysproarggluglu115120125glntyrglyserthrtyrargvalvalservalleuthrvalleuhis130135140glnasptrpleuasnglylysglutyrlyscyslysvalserasnlys145150155160alaleuproalaproileglulysthrileserlysalalysglygln165170175proarggluproglnvaltyrthrleuproproserargaspgluleu180185190thrlysasnglnvalserleuthrcysleuvallysglyphetyrpro195200205seraspilealavalglutrpgluserasnglyglnprogluasnasn210215220tyrlysthrthrproprovalleuaspseraspglyserphepheleu225230235240tyrserlysleuthrvalasplysserargtrpglnglnglyasnval245250255phesercysservalmethisglualaleuhisasnhistyrthrgln260265270lysserleuserleuserproglyglyglyglyglyalaglyglygly275280285glyalaglyglyglyglyalahisproileproaspserserproleu290295300leuglnpheglyglyglnvalargglnargtyrleutyrthraspasp305310315320alaglnglnthrglualahisleugluilearggluaspglythrval325330335glyglyalaalaaspglnserprogluserleuleuglnleulysala340345350leulysproglyvalileglnileleuglyvallysthrserargphe355360365leucysglnargproaspglyalaleutyrglyserleuhispheasp370375380proglualacysserphearggluargleuleugluaspglytyrasn385390395400valtyrglnserglualahisglyleuproleuhiscysproglyasn405410415lysserprohisargaspproalaproargglyprocysargpheleu420425430proleuproglyleuproproalaleuprogluproproglyileleu435440445alaproglnproproaspvalglyserseraspproleusermetval450455460glyglyserglnglyargserprosertyrgluser465470475<210>159<211>480<212>prt<213>人工序列(artificialsequence)<400>159hisserglnglythrphethrserasptyrserlystyrleuaspglu151015glnalaalaglnaspphevalglntrpleumetasnglyglyproser202530serglyalaproproproserglyglyglyglyserglyglyglygly354045serglyglyglyglyseralagluserlystyrglyproprocyspro505560procysproalaproglupheleuglyglyproservalpheleuphe65707580proprolysprolysaspthrleumetileserargthrprogluval859095thrcysvalvalvalaspvalserglngluaspprogluvalglnphe100105110asntrptyrvalaspglyvalgluvalhisasnalalysthrlyspro115120125argglugluglnphealaserthrtyrargvalvalservalleuthr130135140valleuhisglnasptrpleuasnglylysglutyrlyscyslysval145150155160serasnlysglyleuproserserileglulysthrileserlysala165170175lysglyglnproarggluproglnvaltyrthrleuproprosergln180185190gluglumetthrlysasnglnvalserleuthrcysleuvallysgly195200205phetyrproseraspilealavalglutrpgluserasnglyglnpro210215220gluasnasntyrlysthrthrproprovalleuaspseraspglyser225230235240phepheleutyrserargleuthrvalasplysserargtrpglnglu245250255glyasnvalphesercysservalmethisglualaleuhisasnhis260265270tyrthrglnlysserleuserleuserleuglyglyglyglyglyser275280285glyglyglyglyserglyglyglyglyseralahisproileproasp290295300serserproleuleuglnpheglyglyglnvalargglnargtyrleu305310315320tyrthraspaspalaglnglnthrglualahisleugluileargglu325330335aspglythrvalglyglyalaalaaspglnserprogluserleuleu340345350glnleulysalaleulysproglyvalileglnileleuglyvallys355360365thrserargpheleucysglnargproaspglyalaleutyrglyser370375380leuhispheaspproglualacysserphearggluargleuleuglu385390395400aspglytyrasnvaltyrglnserglualahisglyleuproleuhis405410415leuproglyasnlysserprohisargaspproalaproargglypro420425430alaargpheleuproleuproglyleuproproalaleuproglupro435440445proglyileleualaproglnproproaspvalglyserserasppro450455460leusermetvalglyglyserglnglyargserprosertyrgluser465470475480<210>160<211>479<212>prt<213>人工序列(artificialsequence)<400>160hisserglnglythrphethrserasptyrserlystyrleuaspglu151015glnalaalaglnaspphevalglntrpleumetasnglyglyproser202530serglyalaproproproserglyglyglyglyserglyglyglygly354045serglyglyglyglyseralagluserlystyrglyproprocyspro505560procysproalaproglupheleuglyglyproservalpheleuphe65707580proprolysprolysaspthrleumetileserargthrprogluval859095thrcysvalvalvalaspvalserglngluaspprogluvalglnphe100105110asntrptyrvalaspglyvalgluvalhisasnalalysthrlyspro115120125argglugluglnphealaserthrtyrargvalvalservalleuthr130135140valleuhisglnasptrpleuasnglylysglutyrlyscyslysval145150155160serasnlysglyleuproserserileglulysthrileserlysala165170175lysglyglnproarggluproglnvaltyrthrleuproprosergln180185190gluglumetthrlysasnglnvalserleuthrcysleuvallysgly195200205phetyrproseraspilealavalglutrpgluserasnglyglnpro210215220gluasnasntyrlysthrthrproprovalleuaspseraspglyser225230235240phepheleutyrserargleuthrvalasplysserargtrpglnglu245250255glyasnvalphesercysservalmethisglualaleuhisasnhis260265270tyrthrglnlysserleuserleuserleuglyglyglyglyglyala275280285glyglyglyglyalaglyglyglyglyalahisproileproaspser290295300serproleuleuglnpheglyglyglnvalargglnargtyrleutyr305310315320thraspaspalaglnglnthrglualahisleugluilearggluasp325330335glythrvalglyglyalaalaaspglnserprogluserleuleugln340345350leulysalaleulysproglyvalileglnileleuglyvallysthr355360365serargpheleucysglnargproaspglyalaleutyrglyserleu370375380hispheaspproglualacysserphearggluargleuleugluasp385390395400glytyrasnvaltyrglnserglualahisglyleuproleuhiscys405410415proglyasnlys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sglyglnproarggluproglnvaltyr180185190thrleuproproserargaspgluleuthrlysasnglnvalserleu195200205thrcysleuvallysglyphetyrproseraspilealavalglutrp210215220gluserasnglyglnprogluasnasntyrlysthrthrproproval225230235240leuaspseraspglyserphepheleutyrserlysleuthrvalasp245250255lysserargtrpglnglnglyasnvalphesercysservalmethis260265270glualaleuhisasnhistyrthrglnlysserleuserleuserpro275280285glyglyglyglyglyalaglyglyglyglyalaglyglyglyglyala290295300hisproileproaspserserproleuleuglnpheglyglyglnval305310315320argglnargtyrleutyrthraspaspalaglnglnthrglualahis325330335leugluilearggluaspglythrvalglyglyalaalaaspglnser340345350progluserleuleuglnleulysalaleulysproglyvalilegln355360365ileleuglyvallysthrserargpheleucysglnargproaspgly370375380alaleutyrglyserleuhispheaspproglualacysserphearg385390395400gluargleuleugluaspglytyrasnvaltyrglnserglualahis405410415glyleuproleuhisleuproglyasnlysserprohisargasppro420425430alaproargglyproalaargpheleuproleuproglyleupropro435440445alaleuprogluproproglyileleualaproglnproproaspval450455460glyserseraspproleusermetvalglyglyserglnglyargser465470475480proseralaalaser485<210>207<211>460<212>prt<213>人工序列(artificialsequence)<400>207hisserglnglythrphethrserasptyrserlysglnmetaspser151015glnargalaglnaspphevalglntrpleumetasnthrlysargasn202530argasnasnilealaglyglyglyglysergluarglyscyscysval354045glucysproprocysproalaproprovalalaglyproservalphe505560leupheproprolysprolysaspthrleumetileserargthrpro65707580gluvalthrcysvalvalvalaspvalserhisgluaspprogluval859095glnpheasntrptyrvalaspglyvalgluvalhisasnalalysthr100105110lysproargglugluglnpheasnserthrpheargvalvalserval115120125leuthrvalvalhisglnasptrpleuasnglylysglutyrlyscys130135140lysvalserasnlysglyleuproserserileglulysthrileser145150155160lysthrlysglyglnproarggluproglnvaltyrthrleupropro165170175serarggluglumetthrlysasnglnvalserleuthrcysleuval180185190lysglyphetyrproseraspilealavalglutrpgluserasngly195200205glnprogluasnasntyrlysthrthrproprometleuaspserasp210215220glyserphepheleutyrserlysleuthrvalasplysserargtrp225230235240glnglnglyasnvalphesercysservalmethisglualaleuhis245250255asnhistyrthrglnlysserleuserleuserproglyglyglygly260265270glyserglyglyglyglyserhisproileproaspserserproleu275280285leuglnpheglyglyglnvalargglnargtyrleutyrthraspasp290295300alaglnglnthrglualahisleugluilearggluaspglythrval305310315320glyglyalagluaspglnserprogluserleuleuglnleulysala325330335leulysproglyvalileglnileleuglyvallysthrserargphe340345350leucysglnargproaspglyalaleutyrglyserleuhispheasp355360365proglualacysserphearggluargleuleugluaspglytyrasn370375380valtyrglnserglualahisglyleuproleuhiscysproglyasn385390395400lysserprohisargaspproalaproargglyprocysargpheleu405410415proleuproglyleuproproalaleuprogluproproglyileleu420425430alaproglnproproaspvalglyserseraspproleusermetval435440445glyglyserglnglyargserprosertyrgluser450455460<210>208<211>474<212>prt<213>人工序列(artificialsequence)<400>208hisserglnglythrphethrseraspleuserlysglnmetaspser151015argalaalaglnasppheileglutrpleulysasnthrlysargasn202530argasnasnilealaglyglyglyglyserglyglyglyglyserglu354045prolyssercysasplysthrhisthrcysproprocysproalapro505560gluleuleuglyglyproservalpheleupheproprolysprolys65707580aspthrleumetileserargthrprogluvalthrcysvalvalval859095aspvalserhisgluaspprogluvallyspheasntrptyrvalasp100105110glyvalgluvalhisasnalalysthrlysproargglugluglntyr115120125alaserthrtyrargvalvalservalleuthrvalleuhisglnasp130135140trpleuasnglylysglutyrlyscyslysvalserasnlysalaleu145150155160proalaproileglulysthrileserlysalalysglyglnproarg165170175gluproglnvaltyrthrleuproproserarggluglumetthrlys180185190asnglnvalserleuthrcysleuvallysglyphetyrproserasp195200205ilealavalglutrpgluserasnglyglnprogluasnasntyrlys210215220thrthrproprovalleuaspseraspglyserphepheleutyrser225230235240lysleuthrvalasplysserargtrpglnglnglyasnvalpheser245250255cysservalmethisglualaleuhisasnhistyrthrglnlysser260265270leuserleuserproglyglyglyglyglyserglyglyglyglyser275280285glyglyglyglyserhisproileproaspserserproleuleugln290295300pheglyglyglnvalargglnargtyrleutyrthraspaspalagln305310315320glnthrglualahisleugluilearggluaspglythrvalglygly325330335alaalaaspglnserprogluserleuleuglnleulysalaleulys340345350proglyvalileglnileleuglyvallysthrserargpheleucys355360365glnargproaspglyalaleutyrglyserleuhispheaspproglu370375380alacysserphearggluargleuleugluaspglytyrasnvaltyr385390395400glnserglualahisglyleuproleuhiscysproglyasnlysser405410415prohisargaspproalaproargglyprocysargpheleuproleu420425430proglyleuproproalaleuprogluproproglyileleualapro435440445glnproproaspvalglyserseraspproleualametvalglygly450455460serglnglyargserprosertyralaser465470<210>209<211>424<212>prt<213>人工序列(artificialsequence)<400>209gluserlystyrglyproprocysproprocysproalaprogluala151015alaglyglyproservalpheleupheproprolysprolysaspthr202530leumetileserargthrprogluvalthrcysvalvalvalaspval354045serglngluaspprogluvalglnpheasntrptyrvalaspglyval505560gluvalhisasnalalysthrlysproargglugluglnpheasnser65707580thrtyrargvalvalservalleuthrvalleuhisglnasptrpleu859095asnglylysglutyrlyscyslysvalserasnlysglyleuproser100105110serileglulysthrileserlysalalysglyglnproargglupro115120125glnvaltyrthrleuproproserglngluglumetthrlysasngln130135140valserleuthrcysleuvallysglyphetyrproseraspileala145150155160valglutrpgluserasnglyglnprogluasnasntyrlysthrthr165170175proprovalleuaspseraspglyserphepheleutyrserargleu180185190thrvalasplysserargtrpglngluglyasnvalphesercysser195200205valmethisglualaleuhisasnhistyrthrglnlysserleuser210215220leuserleuglyglyglyglyglyalaglyglyglyglyalaglygly225230235240glyglyalahisproileproaspserserproleuleuglnphegly245250255glyglnvalargglnargtyrleutyrthraspaspalaglnglnthr260265270glualahisleugluilearggluaspglythrvalglyglyalaala275280285aspglnserprogluserleuleuglnleulysalaleulysprogly290295300valileglnileleuglyvallysthrserargpheleucysglnarg305310315320proaspglyalaleutyrglyserleuhispheaspproglualacys325330335serphearggluleuleuleugluaspglytyrasnvaltyrglnser340345350glualahisglyleuproleuhisleuproglyasnlysserprohis355360365argaspproalaproargglyproalaargpheleuproleuprogly370375380leuproproalaleuprogluproproglyileleualaproglnpro385390395400proaspvalglyserseraspproleusermetvalglyprosergln405410415glyargserprosertyralaser420<210>210<211>424<212>prt<213>人工序列(artificialsequence)<400>210gluserlystyrglyproprocysproprocysproalaprogluala151015alaglyglyproservalpheleupheproprolysprolysaspthr202530leumetileserargthrprogluvalthrcysvalvalvalaspval354045serglngluaspprogluvalglnpheasntrptyrvalaspglyval505560gluvalhisasnalalysthrlysproargglugluglnpheasnser65707580thrtyrargvalvalservalleuthrvalleuhisglnasptrpleu859095asnglylysglutyrlyscyslysvalserasnlysglyleuproser100105110serileglulysthrileserlysalalysglyglnproargglupro115120125glnvaltyrthrleuproproserglngluglumetthrlysasngln130135140valserleuthrcysleuvallysglyphetyrproseraspileala145150155160valglutrpgluserasnglyglnprogluasnasntyrlysthrthr165170175proprovalleuaspseraspglyserphepheleutyrserargleu180185190thrvalasplysserargtrpglngluglyasnvalphesercysser195200205valmethisglualaleuhisasnhistyrthrglnlysserleuser210215220leuserleuglyglyglyglyglyalaglyglyglyglyalaglygly225230235240glyglyalahisproileproaspserserproleuleuglnphegly245250255glyglnvalargglnargtyrleutyrthraspaspalaglnglnthr260265270glualahisleugluilearggluaspglythrvalglyglyalaala275280285aspglnserprogluserleuleuglnleulysalaleulysprogly290295300valileglnileleuglyvallysthrserargpheleucysglnarg305310315320proaspglyalaleutyrglyserleuhispheaspproglualacys325330335serphearggluargleuleugluaspglytyrasnvaltyrglnser340345350glualahisglyleuproleuhisleuproglyasnlysserprohis355360365argaspproalaproargglyproalaargpheleuproleuprogly370375380leuproproalaleuprogluproproglyileleualaproglnpro385390395400proaspvalglyserseraspproleusermetvalglyglysergln405410415glyargserprosertyrgluser420<210>211<211>424<212>prt<213>人工序列(artificialsequence)<400>211gluserlystyrglyproprocysproprocysproalaprogluala151015alaglyglyproservalpheleupheproprolysprolysaspthr202530leumetileserargthrprogluvalthrcysvalvalvalaspval354045serglngluaspprogluvalglnpheasntrptyrvalaspglyval505560gluvalhisasnalalysthrlysproargglugluglnpheasnser65707580thrtyrargvalvalservalleuthrvalleuhisglnasptrpleu859095asnglylysglutyrlyscyslysvalserasnlysglyleuproser100105110serileglulysthrileserlysalalysglyglnproargglupro115120125glnvaltyrthrleuproproserglngluglumetthrlysasngln130135140valserleuthrcysleuvallysglyphetyrproseraspileala145150155160valglutrpgluserasnglyglnprogluasnasntyrlysthrthr165170175proprovalleuaspseraspglyserphepheleutyrserargleu180185190thrvalasplysserargtrpglngluglyasnvalphesercysser195200205valmethisglualaleuhisasnhistyrthrglnlysserleuser210215220leuserleuglyglyglyglyglyalaglyglyglyglyalaglygly225230235240glyglyalahisproileproaspserserproleuleuglnphegly245250255glyglnvalargglnargtyrleutyrthraspaspalaglnglnthr260265270glualahisleugluilearggluaspglythrvalglyglyalaala275280285aspglnserprogluserleuleuglnleulysalaleulysprogly290295300valileglnileleuglyvallysthrserargpheleucysglnarg305310315320proaspglyalaleutyrglyserleuhispheaspproglualacys325330335serphearggluargleuleugluaspglytyrasnvaltyrglnser340345350glualahisglyleuproleuhiscysproglyasnlysserprohis355360365argaspproalaproargglyprocysargpheleuproleuprogly370375380leuproproalaleuprogluproproglyileleualaproglnpro385390395400proaspvalglyserseraspproleusermetvalglyglysergln405410415glyargserprosertyrgluser420<210>212<211>420<212>prt<213>人工序列(artificialsequence)<400>212gluserlystyrglyproprocysproprocysproalaprogluala151015alaglyglyproservalpheleupheproprolysprolysaspthr202530leumetileserargthrprogluvalthrcysvalvalvalaspval354045serglngluaspprogluvalglnpheasntrptyrvalaspglyval505560gluvalhisasnalalysthrlysproargglugluglnpheasnser65707580thrtyrargvalvalservalleuthrvalleuhisglnasptrpleu859095asnglylysglutyrlyscyslysvalserasnlysglyleuproser100105110serileglulysthrileserlysalalysglyglnproargglupro115120125glnvaltyrthrleuproproserglngluglumetthrlysasngln130135140valserleuthrcysleuvallysglyphetyrproseraspileala145150155160valglutrpgluserasnglyglnprogluasnasntyrlysthrthr165170175proprovalleuaspseraspglyserphepheleutyrserargleu180185190thrvalasplysserargtrpglngluglyasn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pglnserprogluserleuleuglnleulysalaleulysprogly290295300valileglnileleuglyvallysthrserargpheleucysglnarg305310315320proaspglyalaleutyrglyserleuhispheaspproglualacys325330335serphearggluargleuleugluaspglytyrasnvaltyrglnser340345350glualahisglyleuproleuhiscysproglyasnlysserprohis355360365argaspproalaproargglyprocysargpheleuproleuprogly370375380leuproproalaleuprogluproproglyileleualaproglnpro385390395400proaspvalglyserseraspproleusermetvalgluprosergln405410415glyargserprosertyralaser420<210>216<211>424<212>prt<213>人工序列(artificialsequence)<400>216gluserlystyrglyproprocysproprocysproalaprogluala151015alaglyglyproservalpheleupheproprolysprolysaspthr202530leumetileserargthrprogluvalthrcysvalvalvalaspval354045serglngluaspprogluvalglnpheasntrptyrvalaspglyval505560gluvalhisasnalalysthrlysproargglugluglnpheasnser65707580thrtyrargvalvalservalleuthrvalleuhisglnasptrpleu859095asnglylysglutyrlyscyslysvalserasnlysglyleuproser100105110serileglulysthrileserlysalalysglyglnproargglupro115120125glnvaltyrthrleuproproserglngluglumetthrlysasngln130135140valserleuthrcysleuvallysglyphetyrproseraspileala145150155160valglutrpgluserasnglyglnprogluasnasntyrlysthrthr165170175proprovalleuaspseraspglyserphepheleutyrserargleu180185190thrvalasplysserargtrpglngluglyasnvalphesercysser195200205valmethisglualaleuhisasnhistyrthrglnlysserleuser210215220leuserleuglyglyglyglyglyalaglyglyglyglyalaglygly225230235240glyglyalahisproileproaspserserproleuleuglnphegly245250255glyglnvalargglnglutyrleutyrthraspaspalaglnglnthr260265270glualahisleugluilearggluaspglythrvalglyglyalaala275280285aspglnserprogluserleuleuglnleulysalaleulysprogly290295300valileglnileleuglyvallysthrserargpheleucysglnarg305310315320proaspglyalaleutyrglyserleuhispheaspproglualacys325330335serphearggluargleuleugluaspglytyrasnvaltyrglnser340345350glualahisglyleuproleuhisleuproglyasnlysserprohis355360365argaspproalaproargglyproalaargpheleuproleuprogly370375380leuproproalaleuprogluproproglyileleualaproglnpro385390395400proaspvalglyserseraspproleusermetvalglyglysergln405410415glyargserprosertyrgluser420<210>217<211>424<212>prt<213>人工序列(artificialsequence)<400>217gluserlystyrglyproprocysproprocysproalaprogluala151015alaglyglyproservalpheleupheproprolysprolysaspthr202530leumetileserargthrprogluvalthrcysvalvalvalaspval354045serglngluaspprogluvalglnpheasntrptyrvalaspglyval505560gluvalhisasnalalysthrlysproargglugluglnpheasnser65707580thrtyrargvalvalservalleuthrvalleuhisglnasptrpleu859095asnglylysglutyrlyscyslysvalserasnlysglyleuproser100105110serileglulysthrileserlysalalysglyglnproargglupro115120125glnvaltyrthrleuproproserglngluglumetthrlysasngln130135140valserleuthrcysleuvallysglyphetyrproseraspileala145150155160valglutrpgluserasnglyglnprogluasnasntyrlysthrthr165170175proprovalleuaspseraspglyserphepheleutyrserargleu180185190thrvalasplysserargtrpglngluglyasnvalphesercysser195200205valmethisglualaleuhisasnhistyrthrglnlysserleuser210215220leuserleuglyglyglyglyglyalaglyglyglyglyalaglygly225230235240glyglyalahisproileproaspserserproleuleuglnphegly245250255glyglnvalargglnargtyrleutyrthraspaspalaglnglnthr260265270glualahisleugluilearggluaspglythrvalglyglyalaala275280285aspglnserprogluserleuleuglnleulysalaleulysprogly290295300valileglnileleuglyvallysthrserargpheleucysglnarg305310315320proaspglyalaleutyrglyserleuhispheaspproglualacys325330335serphearggluargleuleugluaspglytyrasnvaltyrglnser340345350glualahisglyleuproleuhisleuproglyasnlysserprohis355360365argaspproalaproargglyproalaargpheleuproleuprogly370375380leuproproalaleuprogluproproglyileleualaproglnpro385390395400proaspvalglyserseraspproleusermetvalglyglysergln405410415glyargserproseralaalaser420<210>218<211>424<212>prt<213>人工序列(artificialsequence)<400>218gluserlystyrglyproprocysproprocysproalaprogluala151015alaglyglyproservalpheleupheproprolysprolysaspthr202530leumetileserargthrprogluvalthrcysvalvalvalaspval354045serglngluaspprogluvalglnpheasntrptyrvalaspglyval505560gluvalhisasnalalysthrlysproargglugluglnpheasnser65707580thrtyrargvalvalservalleuthrvalleuhisglnasptrpleu859095asnglylysglutyrlyscyslysvalserasnlysglyleuproser100105110serileglulysthrileserlysalalysglyglnproargglupro115120125glnvaltyrthrleuproproserglngluglumetthrlysasngln130135140valserleuthrcysleuvallysglyphetyrproseraspileala145150155160valglutrpgluserasnglyglnprogluasnasntyrlysthrthr165170175proprovalleuaspseraspglyserphepheleutyrserargleu180185190thrvalasplysserargtrpglngluglyasnvalphesercysser195200205valmethisglualaleuhisasnhistyrthrglnlysserleuser210215220leuserleuglyglyglyglyglyalaglyglyglyglyalaglygly225230235240glyglyalahisproileproaspserserproleuleuglnphegly245250255glyglnvalargglnargtyrleutyrthraspaspalaglnglnthr260265270glualahisleugluilearggluaspglythrvalglyglyalaala275280285aspglnserprogluserleuleuglnleulysalaleulysprogly290295300valileglnileleuglyvallysthrserargpheleucysglnarg305310315320proaspglyalaleutyrglyserleuhispheaspproglualacys325330335serphearggluargleuleugluaspglytyrasnvaltyrglnser340345350glualahisglyleuproleuhiscysproglyasnlysserprohis355360365argaspproalaproargglyprocysargpheleuproleuprogly370375380leuproproalaleuprogluproproglyileleualaproglnpro385390395400proaspvalglyserseraspproleualametvalglyglysergln405410415glyargserprosertyralaser420<210>219<211>420<212>prt<213>人工序列(artificialsequence)<400>219gluserlystyrglyproprocysproprocysproalaprogluala151015alaglyglyproservalpheleupheproprolysprolysaspthr202530leumetileserargthrprogluvalthrcysvalvalvalaspval354045serglngluaspprogluvalglnpheasntrptyrvalaspglyval505560gluvalhisasnalalysthrlysproargglugluglnpheasnser65707580thrtyrargvalvalservalleuthrvalleuhisglnasptrpleu859095asnglylysglutyrlyscyslysvalserasnlysglyleuproser100105110serileglulysthrileserlysalalysglyglnproargglupro115120125glnvaltyrthrleuproproserglngluglumetthrlysasngln130135140valserleuthrcysleuvallysglyphetyrproseraspileala145150155160valglutrpgluserasnglyglnprogluasnasntyrlysthrthr165170175proprovalleuaspseraspglyserphepheleutyrserargleu180185190thrvalasplysserargtrpglngluglyasnvalphesercysser195200205valmethisglualaleuhisasnhistyrthrglnlysserleuser210215220leuserleuglyglyglyglyglyalaglyglyglyglyalaglygly225230235240glyglyalaaspserserproleuleuglnpheglyglyglnvalarg245250255glnargtyrleutyrthraspaspalaglnglnthrglualahisleu260265270gluilearggluaspglythrvalglyglyalaalaaspglnserpro275280285gluserleuleuglnleulysalaleulysproglyvalileglnile290295300leuglyvallysthrserargpheleucysglnargproaspglyala305310315320leutyrglyserleuhispheaspproglualacysserpheargglu325330335argleuleugluaspglytyrasnvaltyrglnserglualahisgly340345350leuproleuhiscysproglyasnlysserprohisargaspproala355360365proargglyprocysargpheleuproleuproglyleuproproala370375380leuprogluproproglyileleualaproglnproproaspvalgly385390395400serseraspproleualametvalglyglyserglnglyargserpro405410415sertyralaser420<210>220<211>424<212>prt<213>人工序列(artificialsequence)<400>220gluserlystyrglyproprocysproprocysproalaprogluala151015alaglyglyproservalpheleupheproprolysprolysaspthr202530leumetileserargthrprogluvalthrcysvalvalvalaspval354045serglngluaspprogluvalglnpheasntrptyrvalaspglyval505560gluvalhisasnalalysthrlysproargglugluglnpheasnser65707580thrtyrargvalvalservalleuthrvalleuhisglnasptrpleu859095asnglylysglutyrlyscyslysvalserasnlysglyleuproser100105110serileglulysthrileserlysalalysglyglnproargglupro115120125glnvaltyrthrleuproproserglngluglumetthrlysasngln130135140valserleuthrcysleuvallysglyphetyrproseraspileala145150155160valglutrpgluserasnglyglnprogluasnasntyrlysthrthr165170175proprovalleuaspseraspglyserphepheleutyrserargleu180185190thrvalasplysserargtrpglngluglyasnvalphesercysser195200205valmethisglualaleuhisasnhistyrthrglnlysserleuser210215220leuserleuglyglyglyglyglyalaglyglyglyglyalaglygly225230235240glyglyalahisproileproaspserserproleuleuglnphegly245250255glyglnvalargglnargtyrleutyrthraspaspalaglnglnthr260265270glualahisleugluilearggluaspglythrvalglyglyalaala275280285aspglnserprogluserleuleuglnleulysalaleulysprogly290295300valileglnileleuglyvallysthrserargpheleucysglnarg305310315320proaspglyalaleutyrglyserleuhispheaspproglualacys325330335serphearggluargleuleugluaspglytyrasnvaltyrglnser340345350glualahisglyleuproleuhisleuproglyasnlysserprohis355360365argaspproalaproargglyproalaargpheleuproleuprogly370375380leuproproalaleuprogluproproglyileleualaproglnpro385390395400proaspvalglyserseraspproleualametvalglyglysergln405410415glyargserprosertyrgluser420<210>221<211>424<212>prt<213>人工序列(artificialsequence)<400>221gluserlystyrglyproprocysproprocysproalaprogluala151015alaglyglyproservalpheleupheproprolysprolysaspthr202530leumetileserargthrprogluvalthrcysvalvalvalaspval354045serglngluaspprogluvalglnpheasntrptyrvalaspglyval505560gluvalhisasnalalysthrlysproargglugluglnpheasnser65707580thrtyrargvalvalservalleuthrvalleuhisglnasptrpleu859095asnglylysglutyrlyscyslysvalserasnlysglyleuproser100105110serileglulysthrileserlysalalysglyglnproargglupro115120125glnvaltyrthrleuproproserglngluglumetthrlysasngln130135140valserleuthrcysleuvallysglyphetyrproseraspileala145150155160valglutrpgluserasnglyglnprogluasnasntyrlysthrthr165170175proprovalleuaspseraspglyserphepheleutyrserargleu180185190thrvalasplysserargtrpglngluglyasnvalphesercysser195200205valmethisglualaleuhisasnhistyrthrglnlysserleuser210215220leuserleuglyglyglyglyglyalaglyglyglyglyalaglygly225230235240glyglyalahisproileproaspserserproleuleuglnphegly245250255glyglnvalargglnargtyrleutyrthraspaspalaglnglnthr260265270glualahisleugluilearggluaspglythrvalglyglyalaala275280285aspglnserprogluserleuleuglnleulysalaleulysprogly290295300valileglnileleuglyvallysthrserargpheleucysglnarg305310315320proaspglyalaleutyrglyserleuhispheaspproglualacys325330335serphearggluargleuleugluaspglytyrasnvaltyrglnser340345350glualahisglyleuproleuhiscysproglyasnlysserprohis355360365argaspproalaproargglyprocysargpheleuproleuprogly370375380leuproproalaleuprogluproproglyileleualaproglnpro385390395400proaspvalglyserseraspproleualametvalglyglysergln405410415glyargserprosertyralaser420当前第1页12