HLA-B57开放型构象异构体的制作方法

人白细胞抗原(hla)属于典型的主要组织相容性复合体(mhc)蛋白家族。hla复合体有助于免疫系统区分身体自身的蛋白质与由诸如病毒和细菌等外来入侵物产生的蛋白质。人类具有三种主要的典型mhci类基因，即hla-a、hla-b和hla-c。典型hla基因有许多可能的变化，允许每个人的免疫系统对广泛的外来入侵物作出反应。某些hla基因具有数百个鉴定版本(等位基因)，每个都被赋予特定数字(诸如hla-b57)。紧密相关的等位基因被分类在一起；例如，至少82个非常相似的等位基因是hla-b57的亚型。这些亚型被指定为hla-b*5701至hla-b*5782，以及紧密相关的hla-b*5801。

典型的mhc-i分子(在人类中指定为hla-i)是三聚体结构，其包含与β2微球蛋白(β2m)和小肽非共价结合的具有三个细胞外结构域(α1、α2和α3)的膜结合重链。hlai重链可以以不与β2微球蛋白或肽结合的形式存在。这些形式被称为开放型构象异构体。

与所有其他hla分子一样，hla-b57的主要功能是将细胞衍生肽呈递给cd8⁺细胞毒性t淋巴细胞(ctl)，作为适应性免疫应答的一部分。在正常生理条件下，hla-b57分子形成由b57重链、β2微球蛋白和肽组成的异源三聚体复合体，所述肽源自自身蛋白、病毒或细菌。在这方面，hla-b57类似于所有其他i类hla等位基因。然而，hla分子还可以作为缺少β2m微球蛋白和肽的游离重链存在于细胞中，并且可称为hla-b57开放型构象异构体(arosa等，openconformers:thehiddenfaceofmhc-imolecules,trendsinimmunology2007mar；28(3):115-23)。

癌症是以经历不受控的破坏性生长的身体异常细胞为特征的一组疾病。癌细胞可以遍布全身并转移而形成肿瘤；这种生长模式被称为恶性。癌症可以通过手术、化学疗法、放射疗法、激素疗法、靶向疗法和免疫疗法来治疗。疗法的选择取决于癌症的类型、癌症的阶段(已传播的程度)、年龄、健康状况和其他个人特征。不存在单一的癌症治疗方法，患者往往接受疗法和姑息护理(palliativecare)的组合。

癌症免疫疗法是指被设计用来诱导患者自身的免疫系统对抗肿瘤的多种治疗策略，并且基于以下见解：免疫系统监视癌症的进展，其涉及多种突变的积累。免疫疗法或者刺激免疫系统的特定细胞组分的活动，或者抵消癌细胞产生的抑制免疫应答的信号(mahoney等，natrevdrugdiscov.2015aug；14(8):561-84)。

不同类型的免疫细胞参与针对癌症的免疫应答。在这个白细胞池(免疫环境(immunecontexture))中，最著名的细胞是：t细胞(细胞毒性cd8⁺t细胞，辅助cd4⁺t细胞-th1、th2和th17表型)，调节t细胞(treg)，巨噬细胞(m1型-促炎性，和m2型-促肿瘤性)，髓系衍生的抑制细胞(mdsc)，自然杀伤细胞(nk细胞)，和树突状细胞(dc)。这些免疫细胞可以位于肿瘤的中心、侵入边缘或相邻的三级淋巴结构中(fridman等，nat.rev.cancer.2012,april:12,298-306)。

免疫微环境的密度和组成在不同的患者中和肿瘤中并不相同。现在已经充分确定，通常，肿瘤浸润m2表型巨噬细胞和髓系衍生的抑制细胞(mdsc)会促进肿瘤进展，而细胞毒性cd8⁺t细胞、th1表型细胞和m1型巨噬细胞的浸润常常与良好的临床结果和对免疫疗法的良好响应相关。其他淋巴和骨髓细胞群的临床影响不太一致，似乎依赖于肿瘤类型和阶段。th17和nk细胞的存在以及肿瘤浸润中treg细胞的缺失/减少与某些癌症适应证的良好结果相关(giraldo等，currentopinioninimmunology2014,27:8-15)。图1中综述了白细胞浸润与临床结果之间的平衡的总览(becht等，currentopinioninimmunology.2016,39:17-13)。

总体而言，调节有利于m1型巨噬细胞、细胞毒性cd8t细胞和th1细胞的浸润、且/或减少mdsc和m2型巨噬细胞的浸润的肿瘤免疫环境是一种治疗癌症的巨大治疗途径，在此通过使用b572-fc蛋白在多种癌症适应证中对其进行了探索。

术语和定义

氨基酸序列以氨基端到羧基端的顺序给出。序列位置的大写字母指单字母代码中的l-氨基酸(stryer，biochemistry，第3版，第21页)。

本说明书中使用的术语“开放型构象异构体”是指未与β2-微球蛋白结合的分离的hla重链分子，无论是作为单体还是作为二聚体(同二聚体或异二聚体)。本文公开的开放型构象异构体的某些实施方式是融合蛋白单体或二聚体，其中hla重链与稳定化多肽区、特别是可结晶片段免疫球蛋白结构域共价连接。

在本说明书的背景下，术语“序列同一性”和“序列同一性百分”比是指通过比较两个比对序列而确定的值。用于进行比较的序列比对方法是本领域公知的。用于进行比较的序列比对可通过以下方法进行：smith和waterman的局部同源性算法(adv.appl.math.2：482(1981))、needleman和wunsch的全局比对算法(j.mol.biol.48：443(1970))、pearson和lipman的相似性检索法(proc.nat.acad.sci.85：2444(1988))或这些算法的计算机化实施形态而，其包括但不限于clustal、gap、bestfit、blast、fasta和tfasta。用于进行blast分析的软件是公众可得的，例如，通过美国国家生物技术信息中心(http：//blast.ncbi.nlm.nih.gov/)。用于比较氨基酸序列的一个实例是使用默认设置的blastp算法：期望阈值：10；字长：3；查询范围内的最大匹配：0；矩阵：blosum62；空位代价：存在11，延伸1；组成调整：条件性组成评分矩阵调整。用于比较核酸序列的一个这样的实例是使用默认设置的blastn算法：期望阈值：10；字长：28；查询范围内的最大匹配：0；匹配/不匹配评分：1.-2；空位代价：线性。除非另有说明，本文提供的序列同一性值是指使用分别利用上述针对蛋白和核酸比较的默认参数的blast程序套件获得的值(altschul等，j.mol.biol.215：403-410(1990))。

在本说明书的背景下，术语“主要组织相容性复合体(mhc)”以其在细胞生物学和生物化学领域中已知的含义使用；它是指展示蛋白质的特定部分(肽)(也称作表位)的细胞表面分子。存在两个主要类别的mhc分子：i类和ii类。

mhci类重链分子通常(即，当不是开放型构象异构体形式时)作为与非mhc分子β2-微球蛋白的单元相连的α链存在。α链在从n末端到c末端的方向上包含信号肽、三个细胞外结构域(α1-3，α1在n末端)、跨膜区和c末端胞质尾。被展示或呈递的肽在α1/α2结构域的中心区域被肽结合沟保持。

在本说明书的背景下，术语β2-微球蛋白结构域以其在细胞生物学和生物化学领域中已知的含义使用；它是指作为mhci类异二聚体分子的一部分的非mhc分子。换句话说，它构成mhci类异二聚体的β链。

在本说明书的背景下，术语人白细胞抗原(hla)以其在细胞生物学和生物化学领域中已知的含义使用；它是指编码人mhci类蛋白的基因座。hla中三个主要的mhci类基因是hla-a、hla-b和hla-c，并且所有这些基因都具有不同数量的等位基因，例如hla-b具有3590个已知等位基因。紧密相关的等位基因合并在某个等位基因的亚组中。例如，等位基因hla-b57具有超过100个紧密相关的等位基因，根据针对hla系统的因子的who命名委员会，这些等位基因被标记为hla-b*57:01:01至hlab*57:82。所有已知的hla基因及其各等位基因的全长或部分序列是本领域技术人员可以在专业数据库中获得的，例如imgt/hla(http：//www.ebi.ac.uk/ipd/imgt/hla/)，并且提供在本说明书的表1中。

在本说明书的上下文中，术语“检查点抑制剂”或“检查点抑制性抗体”意在涵盖能够破坏在t细胞活化后导致t细胞抑制的信号级联(本领域已知的免疫检查点机制的一部分)的试剂、特别是抗体(或抗体样分子)。检查点抑制剂或检查点抑制性抗体的非限制性实例包括针对ctla-4(uniprotp16410)、pd-1(uniprotq15116)、pd-l1(uniprotq9nzq7)、b7h3(cd276；uniprotq5zpr3)、tim-3、gal9、vista、lag3的抗体。

在本说明书的上下文中，术语“检查点激动剂”或“检查点激动剂抗体”意在涵盖能够参与导致t细胞活化的信号级联(本领域已知的免疫检查点机制的一部分)的试剂、特别是但不限于抗体(或抗体样分子)。已知刺激t细胞活化的受体的非限制性实例包括cd122和cd137(4-1bb；uniprotq07011)。术语检查点激动剂或检查点激动剂抗体包括针对cd137(4-1bb)、cd134(ox40)、cd357(gitr)cd278(icos)、cd27、cd28的激动剂抗体。

在本说明书的背景下，术语“抗体”以其在细胞生物学和免疫学领域中已知的含义使用；它是指：完整抗体，包括但不限于免疫球蛋白g型(igg)、a型(iga)、d型(igd)、e型(ige)或m型(igm)；任何抗原结合片段或其单链；以及相关构建体或衍生构建体。完整抗体是包含通过二硫键相连的至少两个重(h)链和两个轻(l)链的糖蛋白。每个重链由重链可变区(vh)和重链恒定区(ch)组成。重链恒定区由ch1、ch2和ch3三个结构域组成。每个轻链由轻链可变区(本文中缩写为vl)和轻链恒定区(cl)组成。轻链恒定区由一个结构域cl组成。重链和轻链的可变区包含与抗原相互作用的结合结构域。抗体的恒定区可以介导免疫球蛋白与包括免疫系统的各种细胞(例如，效应细胞)和经典补体系统的第一组分在内的宿主组织或因子的结合。

在本说明书的上下文中，术语“抗体样分子”是指能够以高亲和力/kd≤10e-8mol/l特异性地结合另一分子或靶标的分子。抗体样分子与其靶标结合，这类似于抗体的特异性结合。术语抗体样分子包括重复蛋白，例如设计的锚蛋白重复蛋白(molecularpartners，zürich)，衍生自犰狳(armadillo)重复蛋白的多肽，衍生自富含亮氨酸的重复蛋白的多肽，和衍生自34肽重复蛋白的多肽。

术语抗体样分子还包括：衍生自蛋白a结构域的多肽，衍生自纤连蛋白结构域fn3的多肽，衍生自共有纤连蛋白结构域的多肽，衍生自脂质运载蛋白的多肽，衍生自锌指的多肽，衍生自src同源结构域2(sh2)的多肽，衍生自src同源结构域3(sh3)的多肽，衍生自pdz结构域的多肽，衍生自γ-晶状体蛋白的多肽，衍生自泛素的多肽，衍生自半胱氨酸结多肽的多肽，和衍生自结状蛋白(knottin)的多肽。

术语蛋白a结构域衍生的多肽是指作为蛋白a的衍生物并且能够特异性结合免疫球蛋白的fc区和fab区的分子。

术语犰狳重复蛋白是指包含至少一个犰狳重复的多肽，其中犰狳重复的特征在于形成发夹结构的一对α螺旋。

在本说明书的背景下，术语可结晶片段(fc)区以其在细胞生物学和免疫学领域中已知的含义使用；它是指包含通过二硫键共价连接的由ch2和ch3结构域组成的两个相同的重链片段的抗体部分。

在本说明书的背景下，术语二聚体是指由两个亚基组成的单元。

在本说明书的背景下，术语同二聚体是指由相同的两个亚基或者由属于同一类亚基的高度相似成员的两个亚基组成的二聚体。同二聚体的一个实例是由独立选自hla-b57等位基因列表中的两个亚基组成的二聚体。在某些实施方式中，同二聚体由两个相同的hla-b57等位基因组成。

在本说明书的背景下，术语“氨基酸连接物”是指长度可变的多肽，其用于连接两个多肽以产生单链多肽。对实施本文指定的本发明有用的连接物的示例性实施方式是由1、2、3、4、5、10、20、30、40或50个氨基酸组成的寡肽链。氨基酸连接物的非限制性实例是连接hla-b57多肽与fc结构域的多肽ggggsggggsggggs。

本发明提供了hla-b57开放型构象异构体。

根据一方面，本发明提供用作药物的hla-b57开放型构象异构体。

根据另一方面，本发明提供了用于预防或治疗癌症或用作免疫调节剂的hla-b57开放型构象异构体。

根据本发明的另一方面，提供了作为药物、更特别而言用于治疗或预防癌症或用作免疫调节剂的分离的hla-b57开放型构象异构体蛋白。

根据本发明的另一方面，提供了分离的hla-b57开放型构象异构体蛋白，其作为免疫调节剂或用作调节t细胞(treg)的负调节剂，用于treg破坏了保护性免疫力的发展的人类疾病中，例如癌症和感染性疾病(vonboehmer等，见上)。

在某些实施方式中，hla-b57开放型构象异构体包含两个相同的hla-b57多肽链。在某些实施方式中，hla-b57开放型构象异构体包含两个不同的hla-b57多肽链。

根据本发明第一方面的替代性方案，提供了hla-b57开放型构象异构体，其用于治疗或预防癌症，或用作免疫调节剂来治疗感染性疾病，特别是用于预防或治疗人类免疫缺陷病毒(hiv)、甲、乙、丙型肝炎病毒(分别为hav、hbv、hcv)、流感病毒、呼吸合胞体病毒(rsv)、麻疹病毒、疱疹病毒和/或黄热病病毒。该方面所述的开放型构象异构体是作为两个单体的二聚体存在的融合蛋白，并且每个单体都独立于另一单体地包含hla-b57链和已知在体内使多肽在代谢上稳定化的多肽结构域。所述稳定化结构域的一个实例是免疫球蛋白的fc(可结晶片段)结构域，特别是γ免疫球蛋白的fc多肽结构域。可选地，hla-b57链和该稳定化结构域可以通过氨基酸连接物接合在一起。下文中将包含hla-b57链和免疫球蛋白fc片段的开放型构象异构体融合蛋白称为hla-b57fc开放型构象异构体或b572-fc。

fc结构域在该融合蛋白中的存在有利于增加溶解度、稳定性、亲合力、半衰期，并且从技术角度来看，在哺乳动物系统中有利于成本有效的生产和纯化(蛋白a或g纯化)。

在某些实施方式中，hla-b57开放型构象异构体同二聚体还包含肽表位片段。

根据本发明的第二方面，提供了用于治疗或预防癌症或用作免疫调节剂的hla-b57开放型构象异构体单体(即，未连接到第二hla-b57重链多肽并且未被β2-微球蛋白结合的hla-b57)。在此方面的某些实施方式中，hla-b57单体还包含肽表位片段。

此方面可总结为以下各项：

第1项：一种分离的单hla-b57重链多肽单体，其基本上不含结合的β2-微球蛋白，其用作药物，特别是用于治疗或预防癌症，或用作免疫调节剂。

第2项：如第1项所述的分离的单hla-b57重链多肽单体，其用于治疗或预防癌症或用作免疫调节剂，其中，所述单体还包含肽表位片段。

第3项：如第1或2项所述的分离的单hla-b57重链多肽单体，其用于治疗或预防癌症或用作免疫调节剂，其中，所述hla-b57链仅由hla-b57α1、α2和α3结构域组成。

第4项：如前述任一项所述的分离的单hla-b57重链多肽单体，其用于治疗或预防癌症或用作免疫调节剂，其中，所述hla-b57链包含跨膜结构域并且不包含细胞内结构域(胞质尾)。

第5项：如前述任一项所述的分离的单hla-b57重链多肽单体，其用于治疗或预防癌症或用作免疫调节剂，其中，所述hla-b57链与表1中所提供的序列中的任一序列具有≥70％、≥80％、≥85％、≥90％、≥92％、≥93％、≥94％、≥95％、≥96％、≥97％或≥98％或100％的序列同一性。

第6项：一种组合药物，其包含：

a.第1～5项中任一项所述的分离的单hla-b57重链多肽单体，和

b.检查点抑制剂，特别是检查点抑制性抗体，和/或检查点激动剂，特别是检查点激动剂抗体。

第7项：如第6项所述的组合药物，其中，所述检查点抑制剂选自ctla4与cd80或cd86相互作用的抑制剂、以及pd-1与其配体pd-l1相互作用的抑制剂，特别是抗ctla4、cd80、cd86、pd-1、pd-l1中的任一种的抗体，更特别是抗人ctla4、pd-1或pd-l1的单克隆抗体；且/或其中，所述检查点激动剂选自针对4-1bb和/或4-1bbl(cd137l,uniprotp41273)的激动剂抗体或配体。

在本发明上述任一方面的某些实施方式中，肽表位片段与hla-b57肽链的抗原呈递结构域内的多肽非共价连接。

在本发明上述任一方面的某些实施方式中，hla-b57链仅包含细胞外hla-b57α1、α2和α3结构域。在这些实施方式中，在本发明的治疗用多肽中不包含hla-b57链的跨膜结构域和细胞内结构域，从而允许其在重组细胞中的胞外表达。通过与注释的hla-b57序列进行逐对序列比对，本领域技术人员甚至可以在先前未知的hla-b57序列中容易地鉴定出相应的结构域。

在本发明上述任一方面的某些实施方式中，同二聚体的hla-b57链选自hla-b*57:01至hla-b*57:82。

在本发明上述任一方面的某些实施方式中，hla-b57链仅包含hla-b57α1、α2和α3结构域，但不包含选自表1的序列的跨膜结构域和细胞内结构域。

在本发明上述任一方面的某些实施方式中，hla-b57链与表1中所提供的序列中的任一序列具有≥70％、≥80％、≥85％、≥90％、≥92％、≥93％、≥94％、≥95％、≥96％、≥97％或≥98％或100％的序列同一性。

在某些实施方式中，hla-b57开放型构象异构体由独立地选自上述hla-b57等位基因的两个亚基组成。在某些实施方式中，同二聚体由两个相同的hla-b57等位基因组成。

在某些实施方式中，hla-b57开放型构象异构体包含fc结构域。在某些具体的实施方式中，fc结构域包含来自免疫球蛋白g型(igg)、a型(iga)、d型(igd)、e型(ige)或m型(igm)的重链恒定区ch2和ch3。

在某些实施方式中，hla-b57开放型构象异构体包含将稳定化结构域(特别是fc结构域)与hla多肽接合在一起的氨基酸连接物。在某些具体的实施方式中，所述氨基酸连接物包含1～50个氨基酸，特别是5～40个氨基酸，更特别是10～30个氨基酸，甚至更特别是15～25个氨基酸，所述连接物将hla-b57链与fc结构域连接为一条单一多肽链。

根据本发明的第三方面，提供了用于治疗癌症或用于癌症疗法中的编码本发明上述方面的hla-b57开放型构象异构体单体、特别是fc开放型构象异构体单体的核酸分子。由所述核酸分子在体内表达所述开放型构象异构体，会在二聚化后产生本发明的融合蛋白多肽。在患者体内由编码药物活性多肽的核酸表达这些药物活性多肽的概念是众所周知的，并且可以赋予患者显著的益处。

在某些实施方式中，所述核酸分子编码包含肽表位片段的hla-b57开放型构象异构体单体、特别是fc开放型构象异构体单体。在某些实施方式中，所述核酸分子编码仅包含细胞外hla-b57α1、α2和α3结构域的hla-b57开放型构象异构体单体、特别是fc开放型构象异构体单体。在某些实施方式中，所述核酸分子编码仅包含细胞外hla-b27α1、α2和α3结构域和肽表位片段的hla-b57开放型构象异构体单体、特别是fc开放型构象异构体单体。

在某些实施方式中，所述核酸分子编码包含氨基酸连接物和/或fc(可结晶片段)结构域的hla-b57开放型构象异构体单体、特别是fc开放型构象异构体单体，并且用于治疗癌症或用于癌症疗法中。

根据本发明的第四方面，提供了用于治疗癌症或用于癌症疗法中的包含本发明第三方面的核酸分子的重组表达载体。

在某些实施方式中，所述重组表达载体是包含在哺乳动物细胞中(特别是在人细胞中)可操纵的启动子的质粒。启动子可操纵地连接到本发明的核酸分子。

根据本发明的另一方面，提供了用于治疗癌症或用于癌症疗法中的包含本发明第三方面的核酸分子的病毒。核酸分子处在在哺乳动物细胞中(特别是在人细胞中)的可操纵的启动子序列的控制下。在某些实施方式中，病毒是腺病毒、腺相关病毒、疱疹病毒或慢病毒。

根据本发明的另一方面，提供了包含本发明第三方面的核酸分子的经体外遗传修饰的宿主细胞。

本发明的另一方面提供了本发明第一和第二方面的hla-b57fc开放型构象异构体同二聚体或融合蛋白同二聚体在制造用于治疗或预防癌症的药物中的应用。

根据另一方面，本发明提供了一种癌症的治疗方法，其包括对有需要的患者施用本发明第一和第二方面的hla-b57fc开放型构象异构体。

根据本发明的另一方面，提供了一种组合药物，其中，所述组合药物包含：

-本发明上述任一方面或实施方式所述的hla-b57开放型构象异构体、特别是hla-b57fc开放型构象异构体，

和

-检查点抑制剂，特别是检查点抑制性抗体，其选自细胞毒性t淋巴细胞相关蛋白4(ctla4；也称为cd152)与cd80或cd86相互作用的抑制剂，程序性细胞死亡蛋白1(pd-1；也称为cd279)与其配体pd-l1相互作用的抑制剂，及含有t细胞免疫球蛋白和含粘蛋白结构域的分子3(tim-3)的配体，

-检查点激动剂，特别是检查点激动剂抗体，其被选择为结合并激活肿瘤坏死因子受体4-1bb(也称为cd137或tnfrsf9)。

在某些实施方式中，免疫检查点抑制剂是ctla4与cd80或cd86相互作用的抑制剂。

在某些实施方式中，免疫检查点抑制剂是易普利姆单抗(ipilimumab)(yervoy；casno.477202-00-9)。

在某些实施方式中，免疫检查点抑制剂是程序性细胞死亡蛋白1(pd-1)与其受体pd-l1相互作用的抑制剂。在某些实施方式中，免疫检查点抑制剂选自临床可用的抗体药物纳武单抗(nivolumab)(bristol-myerssquibb；casno946414-94-4)、派姆单抗(pembrolizumab)(merckinc.；casno.1374853-91-4)，匹迪丽珠单抗(pidilizumab)(casno.1036730-42-3)、阿特朱单抗(atezolizumab)(rocheag；casno.1380723-44-3)和阿维鲁单抗(avelumab)(merckkgaa；casno.1537032-82-8)。

在某些实施方式中，免疫检查点激动剂是尤托米鲁单抗(utomilumab)(pf-05082566)，一种针对4-1bb的全人igg2单克隆抗体，目前正在进行临床试验。

在某些实施方式中，hla-b57开放型构象异构体、特别是hla-b57fc开放型构象异构体以肠胃外剂型提供，特别是加糖后用于注射。在某些实施方式中，检查点抑制剂和/或检查点激动剂作为肠胃外剂型提供，特别是加糖后用于注射。在某些实施方式中，hla-b57开放型构象异构体和检查点抑制剂和/或检查点激动剂均以相同的给药形式存在。

在另一方面，本发明涉及产生重组hla重链多肽的方法。该方法总结为以下各项：

项a：利用重组生物技术方法产生人hla重链多肽的方法，其中所述方法包括以下步骤：

a.表达步骤：在哺乳动物细胞(“生产细胞系”)中共表达：

i.至少编码hla重链的α1链、α2链和α3链的hla编码核酸序列，其处在在细胞(特别是真核细胞，更特别是哺乳动物细胞)中可操纵的启动子序列的控制下，和

ii.编码人hlaβ2微球蛋白(uniprotp61769)的β2-微球蛋白编码核酸序列，其处在在所述细胞(与a.i中相同的细胞)中可操纵的启动子序列的控制下；

b.纯化步骤：从哺乳动物细胞(生产细胞系)中纯化所得的hla重链/β2-微球蛋白复合体；

c.解离步骤：在合适的条件下解离所纯化的hla重链/β2-微球蛋白复合体，并且将hla重链多肽与β2-微球蛋白多肽分离；

d.重折叠步骤：在导致(在具有生理活性的hla开放型构象异构体分子中见到的其天然三级蛋白结构的)重折叠的条件下，温育分离的hla重链多肽。

项b：如项a所述的产生人hla重链多肽的方法，其中，所述hla编码核酸序列从所编码的多肽的n末端到c末端包含α1链、α2链、α3链和稳定化序列。

项c：如项b所述的产生人hla重链多肽的方法，其中，稳定化序列选自牛血清白蛋白和免疫球蛋白恒定片段(fc)，特别是免疫球蛋白g恒定片段，更特别是igg4fc。

项d：如前述任一项所述的产生人hla重链多肽的方法，其中，所述hla编码核酸序列和β2-微球蛋白编码核酸序列存在于相同的核酸载体分子(特别是dna表达质粒)上。

项e：如前述a～c中任一项所述的产生人hla重链多肽的方法，其中，所述hla编码核酸序列和β2-微球蛋白编码核酸序列存在于不同的核酸载体分子(特别是不同的dna表达质粒)上。

项f：如项e所述的方法，其中，相对于包含β2-微球蛋白编码核酸序列的核酸载体，包含hla编码核酸序列的核酸载体以约1倍至5倍过量、特别是1.5倍至5倍过量、特别是约3倍过量而存在。

项g：如前述任一项所述的方法，其中，所述hla编码核酸序列包含免疫球蛋白fc片段作为稳定化序列，且纯化步骤通过将重组hla重链多肽吸附到与蛋白a连接的表面上而实现。

项h：如前述任一项所述的方法，其中，解离步骤通过在酸性条件下、特别是在约ph2的条件下进行处理并在还原条件下进行透析而实现。

项i：如前述任一项所述的方法，其中，重折叠步骤通过在中性条件下进行处理而实现。

更具体地涉及本文所述的b57开放型构象异构体时，所述方法可以总结为以下各项：

项a'：利用重组生物技术方法产生人hla-b57重链多肽的方法，其中所述方法包括以下步骤：

a.表达步骤：在哺乳动物细胞(“生产细胞系”)中共表达：

i.至少编码hla-b57重链的α1链、α2链和α3链的hla-b57编码核酸序列，其处在在细胞(特别是真核细胞，更特别是哺乳动物细胞)中可操纵的启动子序列的控制下，和

ii.编码人hlaβ2微球蛋白(uniprotp61769)的β2-微球蛋白编码核酸序列，其处在在所述细胞(与a.i中相同的细胞)中可操纵的启动子序列的控制下；

b.纯化步骤：从哺乳动物细胞(生产细胞系)中纯化所得的hla-b57重链/β2-微球蛋白复合体；

c.解离步骤：在合适的条件下解离所纯化的hla-b57重链/β2-微球蛋白复合体，并且将hla重链多肽与β2-微球蛋白多肽分离；

d.重折叠步骤：在导致(在具有生理活性的hla开放型构象异构体分子中见到的其天然三级蛋白结构的)重折叠的条件下，温育分离的hla-b57重链多肽。

项b'：如项a'所述的产生人hla-b57重链多肽的方法，其中，所述hla-b57编码核酸序列从所编码的多肽的n末端到c末端包含α1链、α2链、α3链和稳定化序列。

项c'：如项b'所述的产生人hla-b57重链多肽的方法，其中，稳定化序列选自牛血清白蛋白和免疫球蛋白恒定片段(fc)，特别是免疫球蛋白g恒定片段，更特别是igg4fc。

项d'：如前述任一项所述的产生人hla-b57重链多肽的方法，其中，所述hla编码核酸序列和β2-微球蛋白编码核酸序列存在于相同的核酸载体分子(特别是dna表达质粒)上。

项e'：如前述a'～c'中任一项所述的产生人hla-b57重链多肽的方法，其中，所述hla编码核酸序列和β2-微球蛋白编码核酸序列存在于不同的核酸载体分子(特别是不同的dna表达质粒)上。

项f'：如项e'所述的方法，其中，相对于包含β2-微球蛋白编码核酸序列的核酸载体，包含hla编码核酸序列的核酸载体以约1倍至5倍过量、特别是1.5倍至5倍过量、特别是约3倍过量而存在。

项g'：如前述任一项所述的方法，其中，所述hla-b57编码核酸序列包含免疫球蛋白fc片段作为稳定化序列，且纯化步骤通过将重组hla重链多肽吸附到与蛋白a连接的表面上而实现。

项h'：如前述任一项所述的方法，其中，解离步骤通过在酸性条件下、特别是在约ph2的条件下进行处理并在还原条件下进行透析而实现。

项i'：如前述任一项所述的方法，其中，重折叠步骤通过在中性条件下进行处理而实现。

在本文的任何位置将例如等位基因或编码序列等单个可分离特征的替代方式作为“实施方式”列出时，应当理解的是，这些替代方式可以自由组合，以形成本文公开的发明的离散实施方式。

本发明通过以下实施例和附图进一步说明，从中可以得出其他实施方式和优点。这些实施例意在说明本发明，但不限制本发明的范围。

附图说明

图1：描绘了基于肿瘤的免疫细胞浸润而划分的三种不同类型的肿瘤的示意性图示。“免疫原性肿瘤”的特征在于丰富的细胞毒性t淋巴细胞(ctl)浸润、m1型巨噬细胞、三级淋巴结构(tls)的存在以及低/中度血管化，同时与最长的患者存活期相关。“免疫忽视型”肿瘤的特征在于缺乏免疫细胞浸润、低/中度血管化和中等预后。最后，“炎性肿瘤”的特征是丰富的ctl且无tls、m2巨噬细胞有明显浸润、重度血管化和预后不良(becht等，currentopinioninimmunology.2016,39:17-13)。

图2显示出b572-fc阻断小鼠cd4⁺t细胞向itreg转化。以剂量依赖性方式将b572-fc与初始cd4⁺t细胞温育，阻断了向itreg的转化。a)b572-fc以剂量依赖性方式(μg/200μl)阻断cd25(treg的谱系标志物)的表达(c)。b)b572-fc以剂量依赖性方式(μg/200μl)阻断foxp3(tregs的分化标志物)的表达(d)。对照b57-β2m-fc、同种型、补充有tgfβ和il-2的培养基和无补充剂的培养基证明了b572-fc对itreg转化的特异性影响。

图3显示了b572-fc以剂量依赖性方式破坏了鼠treg的抑制。a)来自cd8⁺t细胞和treg的增殖直方图，描绘了b572-fc阻断小鼠treg的抑制并允许cd8⁺t细胞增殖。对照b57-β2m-fc和同种型未改变鼠treg的抑制功能。b)在不同浓度的b572-fc(μg/200μl)下itreg对鼠cd8⁺t细胞的抑制的％。

图4显示了b572-fc抑制淋巴瘤t细胞。a-c)抑制测定，用于确定在(a)对照同种型、(b)对照b57-β2m-fc和(c)b572-fc的存在下的细胞增殖。与对照细胞系相比，b572-fc以剂量依赖性方式(μg/200μl)抑制人(jurkat)和小鼠(eg.7)淋巴瘤细胞系。

图5显示了b572-fc与白细胞群的不同免疫调节受体的相互作用。a)kir3dl1(在nk细胞和t细胞亚群中表达)；b)kir3dl2(在nk细胞和t细胞亚群中表达)；c)kir3dl3(在nk细胞和t细胞亚群中表达)；d)lilrb1(在nk细胞、t细胞、单核细胞和巨噬细胞的群体中表达)；e)lilrb2(主要在巨噬细胞和mdsc中表达)；和f)pirb(lilrb2的鼠同源物)，通过酶联免疫吸附测定(elisa)测得。

图6显示了b57-fc和β2mdna盒的示意图，以及b57-β2m-fc分子在cho细胞中的表达。a)插入人igg4-fc载体盒中的hla-b57重链的α1、2和3结构域；和插入单独的载体盒中的人β2微球蛋白。b)中国仓鼠卵巢细胞(cho)中的转染使用1:1比例的b57-fc载体+β2m载体进行，用于细胞外产生b57-β2m-fc蛋白。收集上清液并使用标准抗体纯化方案纯化b57-β2m-fc。从b57-β2m-fc复合物中除去β2m，然后将b57-fc单体重折叠形成b572-fc同二聚体。

图7显示了b572-fc与pd-1抗体的组合减小了c38鼠同系结肠癌模型中的肿瘤尺寸。a)结肠癌细胞(c38)的注射时间点和化合物注射的实验设计。b)治疗组(n＝6)的平均肿瘤体积mm³。c)与同种型相比，b572-fc和pd-1治疗组的肿瘤抑制百分比。注射物质的实验设计如下：载体pbsq3dx7，同种型(10mg/kg)q3dx7；b572-fc(10mg/kg)q3dx7；pd-1biwk×2(200μg)；和b572-fc+pd-1(分别为q3dx7和biwk×2)。肿瘤体积表示为平均值±sem，并通过双因素anova来分析，然后进行bonferroni事后分析，**p<0.01。q＝注射之间的天数；dx＝注射次数，biwk＝每周两次。

图8显示了b572-fc与pd-1抗体的组合减小了胰腺(pan02)癌小鼠模型中的肿瘤尺寸。a)胰腺癌细胞(pan02)的注射时间点和化合物注射的实验设计。b)用b572-fc和/或pd-1的治疗组(n＝8)的平均肿瘤体积mm³。注射物质的实验设计如下：同种型(5mg/kg)biwk×3；b572-fc(5mg/kg)biwk×3；pd-1(5mg/kg)biwk×3；和b572-fc+pd-1(biwk×3)。肿瘤体积表示为平均值±sem，并通过双因素anova来分析，然后进行bonferroni事后分析，*p<0.05；**p<0.01；****p<0.0001。biwk＝每周两次。

图9显示了b572-fc与pd-l1抗体的组合减小了胰腺(pan02)癌小鼠模型中的肿瘤尺寸。a)用b572-fc和/或pd-l1的治疗组(n＝8)的平均肿瘤体积mm³。b)与同种型相比，b572-fc、pd-1和pd-l1治疗组的肿瘤抑制百分比。注射物质的实验设计如下：同种型(5mg/kg)biwk×3；b572-fc(5mg/kg)biwk×3；pd-l1(5mg/kg)biwk×3；和b572-fc+pd-l1(biwk×3)。肿瘤体积表示为平均值±sem，并通过双因素anova来分析，然后进行bonferroni事后分析，*p<0.05；**p<0.01；****p<0.0001。biwk＝每周两次。

图10显示了通过流式细胞术对肿瘤中的浸润白细胞进行的免疫背景分析，所述肿瘤来自用b572-fc和pd-1治疗的胰腺(pan02)癌小鼠。所分析的浸润肿瘤的相关白细胞：a)nk细胞；b)cd8/treg比例；和c)髓系衍生的抑制细胞(mdsc)；白细胞数表示为平均值±sem，并通过单因素anova来分析，然后进行turkey事后分析，*p<0.05。

图11显示了通过流式细胞术对肿瘤中的浸润白细胞进行的免疫背景分析(图10的后续)，所述肿瘤来自用b572-fc和pd-1治疗的胰腺(pan02)癌小鼠。所分析的浸润肿瘤的相关白细胞：a)巨噬细胞，和b)巨噬细胞m1/m2比例。白细胞数表示为平均值±sem，并通过单因素anova来分析，然后进行turkey事后分析，*p<0.05；**p<0.01；***p<0.001。

图12显示了通过流式细胞术对肿瘤中的浸润白细胞进行的免疫背景分析，所述肿瘤来自用b572-fc和pd-l1治疗的胰腺(pan02)癌小鼠。所分析的浸润肿瘤的相关白细胞：a)nk细胞；b)cd8/treg比例；和c)髓系衍生的抑制细胞(mdsc)。白细胞数表示为平均值±sem，并通过单因素anova来分析，然后进行turkey事后分析，*p<0.05。

图13显示了通过流式细胞术对肿瘤中的浸润白细胞进行的免疫背景分析(图12的后续)，所述肿瘤来自用b572-fc和pd-l1治疗的胰腺(pan02)癌小鼠。所分析的浸润肿瘤的相关白细胞：a)巨噬细胞，和b)巨噬细胞m1/m2比例。白细胞数表示为平均值±sem，并通过单因素anova来分析，然后进行turkey事后分析，*p<0.05；**p<0.01。

图14显示了b572-fc与4-1bb检查点激动剂抗体的组合减小了黑色素瘤(b16f10)癌小鼠模型中的肿瘤尺寸。a)黑色素瘤癌细胞(b16f10)的注射时间点和化合物注射的实验设计。b)用b572-fc和/或4-1bb抗体的治疗组(n＝8)的平均肿瘤体积mm³。注射物质的实验设计如下：同种型(5mg/kg)biwk3次注射；b572-fc(5mg/kg)biwk3次注射；4-1bb抗体(1mg/kg)biwk×3次注射；和b572-fc+4-1bbbiwk3次注射。肿瘤体积表示为平均值±sem，并通过双因素anova来分析，然后进行bonferroni事后分析，**p<0.01；****p<0.0001。biwk＝每周两次。

图15显示了b572-fc与4-1bb检查点激动剂抗体的组合以及与pd-1拮抗性抗体的组合减小了黑色素瘤(b16f10)癌小鼠模型中的肿瘤尺寸(图14的实验的后续)。a)用b572-fc、pd-1和4-1bb抗体的治疗组(n＝8)的平均肿瘤体积mm³。b)与同种型相比，b572-fc、4-1bb和pd-1治疗组的肿瘤抑制百分比。注射物质的实验设计如下：同种型(5mg/kg)biwk3次注射；b572-fc(5mg/kg)biwk3次注射；4-1bb抗体(1mg/kg)biwk×3次注射；pd-1biwk3次注射(5mg/kg)；和b572-fc+4-1bbbiwk3次注射，b572-fc+pd-1biwk3次注射，pd-1+4-1bbbiwk3次注射，和b572-fc+4-1bb+pd-1biwk3次注射。肿瘤体积表示为平均值±sem。biwk＝每周两次。

图16显示了通过流式细胞术对来自经治疗的黑色素瘤(b16f10)小鼠的肿瘤中的浸润白细胞进行的免疫背景分析。所分析的浸润肿瘤的相关白细胞：a)nk细胞；b)cd8/treg比例；和c)髓系衍生的抑制细胞(mdsc)。白细胞数表示为平均值±sem，并通过单因素anova来分析，然后进行turkey事后分析，*p<0.05；**p<0.01；***p<0.001；****p<0.0001。

图17显示了通过流式细胞术对来自经治疗的黑色素瘤(b16f10)小鼠的肿瘤中的浸润白细胞进行的免疫背景分析(图16的后续)。所分析的浸润肿瘤的相关白细胞：a)巨噬细胞，和b)巨噬细胞m1/m2比例。白细胞数表示为平均值±sem，并通过单因素anova来分析，然后进行turkey事后分析，*p<0.05；**p<0.01；***p<0.001。

实施例

发明人惊奇地发现hla-b57开放型构象异构体与nk、t细胞、髓系衍生细胞(巨噬细胞和mdsc)中存在的不同免疫调节表面受体相互作用，并在体外调节treg的分化和抑制功能。

发明人惊奇地发现hla-b57开放型构象异构体，特别是当作为包含fc免疫球蛋白片段的融合蛋白存在时，可用于癌症疗法中。hla-b57-fc分子可以单独使用或与其他癌症治疗剂组合使用。

此外，发明人发现了b572-fc注射作为单一疗法或作为使用检查点抑制剂或激动剂抗体的组合方法的一种新的体内作用模式。单独或组合的b572-fc治疗可以调节多种类的白细胞向肿瘤的浸润，这通过增加的m1/m2细胞比例、增加的nk细胞浸润、增加的cd8⁺t细胞/treg比例和减少的mdsc浸润来确定。总体而言，b572-fc单独或与拮抗/激动剂抗体的组合方法的作用模式无疑在癌症治疗中是相关的，并且与癌症免疫疗法中当前的临床需求相关。

hla-b57fc开放型构象异构体可用作靶向以免疫调节作为治疗方法的疾病的治疗剂，如在癌症和传染病的情况中那样。

体外测试

b572-fc分子能够通过阻断itreg分化并对treg抑制产生负面影响来调节免疫应答(图2-3)。

b572-fc阻断鼠cd4⁺t细胞向itreg的转化

以剂量依赖性方式(μg/ml)分析hla对原始cd4⁺t细胞的itreg转化的影响，其中将b572-fc、b57-β2m-fc、同种型和pbs与原始cd4⁺t细胞在用于itreg转化的最佳培养条件下温育。证明了b572-fc向下调节对cd25(图2a,c)和foxp3(图2b,d)的诱导。

b572-fc破坏了treg对小鼠cd8⁺t细胞的抑制

使用紫色标记的初始cd8⁺t细胞作为应答细胞，确定了鼠treg的抑制功能(图3)。将treg与b572-fc以及对照b57-β2m-fc和同种型抗体共培养，96小时后测量cd8⁺t细胞的增殖。单独的cd8⁺t细胞显示出强烈的增殖，并且如所预期的，当与对照(b57-β2m-fc和同种型)温育时，treg细胞抑制了cd8⁺t细胞的增殖。值得注意的是，在b572-fc的存在下，cd8⁺t细胞的强烈增殖表明treg的抑制功能受到极大破坏(图3a)。b572-fc的效果是剂量依赖性的(图3b)。

b572-fc破坏了白血病t细胞的增殖。

我们确定了b572-fc增殖效应在不同癌细胞系中的效果(图4)。结果表明，与对照物b57-β2m-fc或同种型igg4相比，b572-fc调节淋巴瘤t细胞系的增殖，表明其作为靶向疗法用于治疗淋巴瘤的潜在应用。

b572-fc结合在多种类型的白细胞中表达的免疫调节受体

我们用酶联免疫吸附测定(elisa)确定了b572-fc是否与特定的免疫调节受体相互作用。结果证明b572-fc与kir3dl1、kir3dl2、kir3dl3、lilrb1、lilrb2和pirb受体相互作用，作用方式与其b57-β2m-fc对照物不同(图5a-d)。此外，我们还比较了b272-fc和b27-β2m-fc，以证明相似的hla开放型构象异构体分子是否以不同的亲和力与相同的受体相互作用。

在cho细胞中产生作为人fc融合蛋白的b57开放型构象异构体

从治疗的角度来说，有效的策略是以稳定的形式(fc融合)产生hla-b57开放型构象异构体分子，以增加溶解性、稳定性、亲合力、半衰期，并且从技术角度来说，在哺乳动物系统中进行成本有效的生产和纯化。与b57-β2m-fc蛋白质的细胞外产生所必需的人β2m载体一起，将hla-b57的α1、α2和α3结构域插入到人igg4-fc载体盒(图6a)中，成功地产生了b57-β2m-fc复合体(图6a，b)。以1:1的比例使用b57-fc-载体+β2m载体，在中国仓鼠卵巢细胞(cho)中进行转染。收集上清液，并且使用标准抗体纯化方案(recombinantproteinpurificationhandbook,principlesandmethods.2009.gehealthcare,18-1142-75)纯化b57-β2m-fc(图6b)。通过sec或透析方法使用变性条件进行β2m与b57-fc游离重链的分离。在重折叠缓冲液中使用稀释法评估b572-fc的重折叠，并通过蛋白质印迹进行分析(数据未示出)。

在多种同系结肠癌小鼠模型中对b572-fc与pd-1、pd-l1和4-1bb抗体进行临床前联合疗法试验

在鼠结肠癌(c38)、胰腺癌(pan02)和黑色素瘤(b16-f10)同系小鼠模型中展示了对作为免疫调节治疗性分子的b572-fc进行的体内概念验证研究，其作为单一疗法以及与pd-1、pd-l1或4-1bb抗体的组合。

对于结肠癌模型，按照已建立的方案，将c38片段肿瘤皮下注射到同系小鼠的胁腹中。一旦肿瘤达到约80mm³(肿瘤移植后1-2周)，根据其肿瘤体积对小鼠进行统计学分配。腹膜内注射b572-fc，每3天七次(q3dx7)；pd-1注射4次，每周2次(biwk×2)(图7a)。

在结肠癌(c38)中，数据证明b572-fc与pd-1抗体的组合显著减小了肿瘤(图7b)。组合疗法b572-fc+pd-1与同种型对照抗体相比显著减小了肿瘤体积(分别为333mm³和2120mm³，p<0.01)。另外，组合疗法b572-fc+pd-1与pd-1单一疗法相比也显示出显著的肿瘤尺寸减小(分别为333mm³和1423mm³，p<0.01)(图7b)。b572-fc单一疗法或pd-1单一疗法在实验结束时与同种型对照相比无差异，但在第24天，经b572-fc治疗的小鼠与同种型显著不同(384mm³vs652mm³，p<0.05)，pd-1与同种型也显著不同(151mm³vs652mm³，p<0.01)(图7b)，表明b572-fc单一疗法对结肠癌小鼠的肿瘤进展也具有免疫调节作用。

对于胰腺(pan02)和黑色素瘤(b16f10)小鼠模型，按照已建立的方案，分别将细胞以1x10⁵注射到同源小鼠的右胁腹中。一旦肿瘤达到约80mm³(注射细胞后1-2周)，根据其肿瘤体积对小鼠进行统计学分配(图8a、14a)。

在胰腺(pan02)中，数据证明b572-fc单一疗法和与pd-1抗体的组合能够显著减小肿瘤(图8b、9b)。组合疗法b572-fc+pd-1与同种型对照抗体相比展示出了显著减小的肿瘤体积(分别为216mm³和799mm³，p<0.0001)(图8b)。另外，组合疗法b572-fc+pd-1与pd-1单一疗法相比也显示出显著的肿瘤尺寸减小(分别为216mm³和445mm³，p<0.01)(图8b)。b572-fc单一疗法与同种型相比显著不同(分别为545mm³和799mm³，p<0.05)。pd-1单一疗法与同种型相比显著不同(分别为445mm³和799mm³，p<0.0001)(图8b)。

在胰腺(pan02)中，b572-fc与pd-l1抗体的组合显著减小了肿瘤(图9a-b)。组合疗法b572-fc+pd-l1与同种型相比显示出显著的肿瘤尺寸减小(分别为397mm³和799mm³，p<0.0001)(图9a)。pd-l1单一疗法与同种型相比显著不同(分别为531mm³和799mm³，p<0.01)(图9a)。

胰腺(pan02)小鼠的肿瘤免疫背景证明了b572-fc疗法对多种肿瘤浸润性白细胞的影响(图10-13)。b572-fc单一疗法与对照同种型相比增加了nk细胞的浸润(p<0.05)(图10a)，并且通过有利于m1型巨噬细胞在肿瘤内的存在而显著改变了巨噬细胞m1/m2细胞比例(p<0.05)(图11b)。b572-fc与pd-1的组合疗法与pd-1单一疗法相比显著降低了肿瘤中mdsc细胞的浸润(p<0.05)(图10c)，减少了巨噬细胞的浸润(图11a)(p<0.05)，并且与同种型和pd-1单一疗法相比显著改变了巨噬细胞m1/m2比例(图11b)(p<0.001)。b572-fc与pd-l1的组合疗法(图12-13)与同种型(p<0.01)和pd-l1(p<0.05)相比显著改变了巨噬细胞m1/m2细胞比例(图13e)。

在黑色素瘤(b16f10)中，数据证明b572-fc与4-1bb激动剂抗体组合能够显著减小肿瘤(图14-15)。组合疗法b572-fc+4-1bb与同种型对照抗体相比展示出了显著不同的肿瘤体积减小(分别为756mm³和1424mm³，p<0.0001)(图14b)。另外，组合疗法b572-fc+4-1bb与4-1bb单一疗法相比也显示出显著的肿瘤尺寸减小(分别为756mm³和1199mm³，p<0.01)(图14b)。4-1bb单一疗法与同种型相比没有显著不同(分别为1199mm³和1424mm³)。pd-1单一疗法和组合疗法在各组之间并未显示出显著性(图15a)。然而，三联组合疗法(b572-fc+4-1bb+pd-1)与同种型相比显示出非常显著的差异(p<0.0001)，但并未优于组合b572-fc+4-1bb(图15a-b)。

经治疗的黑色素瘤(b16f10)小鼠的肿瘤免疫背景证明了b572-fc疗法对多种肿瘤浸润性白细胞的影响(图16-17)。与同种型相比，b572-fc单一疗法显著降低了肿瘤内mdsc细胞的存在(p<0.05)(图16c)。通过cd8⁺t细胞/treg之比测得，b572-fc与4-1bb抗体的组合疗法显著改变了cd8⁺t细胞相对于treg细胞的存在(p<0.05)(图16b)，显著降低了肿瘤内mdsc细胞的存在(p<0.05)(图16c)，并且与同种型和4-1bb单一疗法相比，显著改变了巨噬细胞m1/m2的细胞比例(p<0.05)(图17b)。b572-fc与4-1bb抗体和pd-1抗体的三联组合疗法显著诱导了nk细胞向肿瘤的浸润(p<0.05)(图16a)，与同种型相比显著改变了cd8⁺t细胞/treg之比(分别为158％和23％，p<0.0001)，并且与所有其他组相比也是如此(图16b)。此外，与所有其他组相比，还显著减少了肿瘤内mdsc细胞的存在(p<0.001)(图16c)，并显著改变了巨噬细胞m1/m2的细胞比例(图17b)。

结论

使用结肠、胰腺和黑色素瘤的临床前同系小鼠模型证明了使用b572-fc分子对抗癌症的原理证据。本文的数据证明了b572-fc作为单一疗法和/或与多种检查点抑制剂和/或检查点激动剂(例如pd-1、pd-l1或4-1bb抗体)的组合疗法的治疗潜力。

还通过建立白细胞的肿瘤浸润而在胰腺和黑色素瘤小鼠模型中体内评估了b572-fc的作用模式。b572-fc疗法能够调节多种白细胞向小鼠肿瘤的浸润，这通过增加的m1/m2细胞比例、减少的mdsc浸润、增加的cd8⁺t细胞/treg比例和增加的nk细胞浸润来确定。总体而言，b572-fc单独或与拮抗/激动剂抗体的组合方法的作用模式无疑在癌症治疗中是相关的，并且与癌症免疫疗法中当前的临床需求相关。

b572-fc作为一类新的免疫调节药物而出现。体外和体内数据指向如下机制：b572-fc分子充当激活抗肿瘤免疫力的开通机制。不希望受理论束缚，发明人推测hla-b57开放型构象异构体与髓系细胞(巨噬细胞、mdsc)、t细胞和nk细胞中存在的多种免疫调节受体结合并相互作用，协同参与并加剧免疫应答。

材料和方法

动物和细胞系

使用小鼠来源的结肠癌c38细胞系、胰腺导管腺癌pan02小鼠细胞系和黑色素瘤b16f10小鼠细胞系在c57bl/6小鼠中进行体内实验。

体外实验细胞系：eg.7，小鼠t细胞淋巴瘤；jurkat，人t细胞淋巴瘤；l428，人霍奇金淋巴瘤；l540，人霍奇金淋巴瘤；l1236，人霍奇金淋巴瘤；daudi，b细胞淋巴瘤；imr-5，神经母细胞瘤；sk-n-as，神经母细胞瘤；和m130428，黑色素瘤。

体内治疗

在第6周，将c38肿瘤片段皮下注射到同系雌性c57bl/6小鼠的右侧肋腹中。在第6周，将pan02和b16f10细胞系以1×10⁵注射到同系小鼠的右侧胁腹中。一旦肿瘤在结肠(c38)、胰腺(pan02)和黑色素瘤(b16f10)中达到±80mm³，根据它们各自的肿瘤体积大小分配动物并分组，它们之间没有显示出统计学差异。使用卡尺测量肿瘤直径，根据公式d/2×d²计算体积，其中d和d分别是以毫米为单位的肿瘤的最长直径和最短直径。

对于结肠(c38)，细胞注射时间点和物质注射的实验设计如下：载体(pbs200μl)；同种型(10mg/kg)q3dx7；b572-fc(10mg/kg)；pd-1biwk×2(200μg)；b572-fc+pd-1(分别为q3dx7和biwk×2)；b272-fc+pd-1(分别为q3dx7和biwk×2)。对于胰腺(pan02)，注射物质的实验设计如下：同种型(5mg/kg)biwk×3；b572-fc(5mg/kg)biwk×3；pd-1biwk×3(5mg/kg)；pd-l1biwk×3(5mg/kg)；b572-fc+pd-1(biwk×3)和b572-fc+pd-l1(biwk×3)。对于黑色素瘤(b16f10)，注射物质的实验设计如下：同种型(5mg/kg)biwk3次注射；b572-fc(5mg/kg)biwk3次注射；4-1bb抗体(1mg/kg)biwk3次注射；pd-1biwk3次注射(5mg/kg)；b572-fc+4-1bbbiwk3次注射，b572-fc+pd-1biwk3次注射，pd-1+4-1bbbiwk3次注射，和b572-fc+4-1bb+pd-1biwk3次注射。

用于流式细胞术的肿瘤样品使用ebioscience描述的方案(https://www.ebioscience.com/media/pdf/best-protocols/cell-preparation-for-flow-cytometry.pdf，于2017年2月21日访问)制备。

抗体

将用于体外测试的白细胞小鼠群体用以下染色：cd3(pe-cy7-ebioscience)，cd4(fitc-bdbioscience)，foxp3+(efluor450-ebioscience)，cd45(percp-ebioscience)，cd3(pe-ebioscience)，nk1.1(bv421-ebioscience)，cd11b(fitc-ebioscience)，cd11c(fitc-ebioscience)，cd25(pe-cy7-biolegend)。

与hla-b和-c等位基因的无β2m重链结合并因此与b572结合的hc10mab(igg2a)由hiddeploegh博士(mit，ma)馈赠。

将来自肿瘤样品的流式细胞术抗体用以下染色：cd45(fitc；克隆30-f11；biolegend)，cd3(percp/cy5.5；克隆17a2；biolegend)，cd4(bv510；克隆gk1.5；biolegend)，cd8(apc-h7；克隆53-6.7；bd)，foxp3(pe；克隆fjk-16s；ebioscence)，cd11b(bv650；克隆m1/70；biolegend)，f4/80(pe/cy7；克隆bm8；biolegend)，gr-1(apc-r700；克隆rb6-8c5；bd)，nk1.1(bv605；克隆pk136；biolegend)，cd206(apc；克隆c068c2；biolegend)，cd86(bv421；克隆gl-1；biolegend)，l/d染色(buv395；invitrogen)。

检查点抑制剂抗体抗小鼠pd-1克隆rmp1-14获自bioxcell。检查点抑制剂抗体抗小鼠pd-1克隆10f.9g2获自bioxcell。激动剂抗体抗小鼠4-1bb克隆3h3获自bioxcell。

白细胞的流式细胞术分析

使用facscantoii(bdbioscience)进行流式细胞术分析，并使用flowjo7.6.4版来分析数据。

treg的产生

为了在鼠cd4⁺t细胞中诱导foxp3的表达，我们从c57bl/6脾细胞中收获脾脏细胞，并进行纯化(小鼠初始cd4⁺t细胞分离试剂盒-easysep)以获得cd4⁺初始t细胞。然后，在涂布有5μg/ml抗cd3mab(ebioscience)、可溶性2μg/ml抗cd28mab(biolegend)、10μg/mltgf-β1(r&dsystems)和100iu/mlil-2(r&dsystems)的96孔板中，将以10⁵个细胞/200μl/孔培养细胞96小时。

b572-fc存在下的itreg转化

在不同剂量浓度(μg/200μl)的b572-fc、b57-β2m-fc、b27-β2m-fc、同种型igg4和pbs的存在下在用于itreg转化的最佳培养条件下温育鼠初始cd4⁺t细胞72小时。通过流式细胞术测量itreg转化。

抑制测定

cd4⁺或cd8⁺t效应细胞是来自小鼠或人的纯化的pbmc(小鼠初始cd4⁺t细胞分离试剂盒-easysep；flowcomp^tm小鼠cd8-lifetechnologies；cd8人-lifetechnologies)，并且标记有10μm细胞痕量紫增殖染料(molecularprobes)。在涂布有cd3(ebioscience)(3μg/ml)和可溶性cd28(ebioscience)(1μg/ml)抗体的96孔u形底平板中，培养treg(2.5×10⁴)细胞和t效应细胞(2.5×10⁴)96小时。使用facscantoii测量t效应细胞的增殖，并使用flowjo7.6.4版的增殖分析软件分析数据。

增殖测定

在加入不同浓度(10、5和2μg/孔)的药物1天后，将细胞以5×10⁵个细胞/孔的密度平板接种在圆形96孔板中。根据手册说明书(细胞增殖试剂盒ii，roche)进行xtt增殖测定。使用微孔板读数器在450nm下以孔的吸光度获取结果。

elisa测定

使用涂布有10μg/ml选定的重组白细胞受体(人kir3dl1、人kir3dl2、人kir3dl3、人lilrb1、人lilrb2和小鼠pirb)的maxisorp(nunc，switzerland)96孔板进行竞争elisa测定。将受体在4℃温育过夜，用5％乳粉-pbs封闭2小时。以2μg/ml添加b572-fc、b57-β2m-fc、b272-fc、b27-β2m-fc和同种型igg4，室温下保持2小时。将针对人fc的hrp缀合抗体用作检测剂。

b572-fc的产生、纯化和重折叠

通过将hla-b57的α1、α2和α3结构域插入人igg4-fc载体(invivogen)中，并利用单独载体中的人β2-微球蛋白(β2m)，实现了b57-β2m-fc的重组产生。通过将b57-fc载体和β2m载体共转染到中国仓鼠卵巢(cho)细胞中来进行重组b57-β2m-fc的产生。b57-β2m-fc的产生外包给evitriaag。

使用常规的抗体纯化方案进行b57-β2m-fc的纯化。添加变性步骤从b57-β2m-fc复合体中除去β2m，来进行b572-fc的产生。

简言之，在使上清液流过(5ml/min)蛋白g柱(amershampharmacia)后，进行b57-β2m-fc的捕获步骤。使用洗脱缓冲液(100mm甘氨酸，ph2.0)从蛋白g柱中洗脱出b57-β2m-fc，并在8m尿素、100mmtris-hclph8.0中回收级分，由此进行中间纯化步骤。第一精制步骤：通过使用具有系统(gelifescience)的superdex200制备级或sephacryls-100hr(gelifescience)尺寸排阻色谱(sec)，或者通过用30kda或50kda孔径的膜(millipore)进行透析，将b57-fc单体级分与β2m分离。对b57-fc单体进行间隔8小时的3次脉冲，每次在100倍体积的重折叠缓冲液(50mmtris-hclph8.5、500mml-精氨酸、1mmedta、0.15mmnacl、1％蔗糖、0.01％tween-80)中进行，之后，通过稀释法使从两种方案回收的b57-fc单体重折叠。通过sec进行第二精制步骤以进一步除去杂质，并将新回收的b572-fc分子级分的缓冲液交换成稀释缓冲液(pbs、1％蔗糖、0.01％tween-20)。使用0.2μm膜(millipore)对纯化的b572-fc的溶液进行过滤灭菌。

通过sds聚丙烯酰胺凝胶电泳(sds-page)和使用hc10(对hla游离重链有特异性)抗体的蛋白质印迹来分析b57-β2m-fc复合体和b572-fc的级分。使用和不使用变性条件(10mmdtt)进行β2m的蛋白质印迹(数据未示出)。

hla-b57等位基因的全长和部分序列

全长hla-527α链的功能性结构域从n末端至c末端为：信号肽，α1，α2，α3，跨膜结构域，和胞质尾。

表1：hla-b57等位基因

序列表

<110>苏黎世大学

巴塞尔大学

<120>hla-b57开放型构象异构体

<130>uz271wo

<160>109

<170>patentinversion3.5

<210>1

<211>362

<212>prt

<213>homosapiens

<400>1

metargvalthralaproargthrvalleuleuleuleutrpglyala

151015

valalaleuthrgluthrtrpalaglyserhissermetargtyrphe

202530

tyrthralametserargproglyargglygluproargpheileala

354045

valglytyrvalaspaspthrglnphevalargpheaspseraspala

505560

alaserproargmetalaproargalaprotrpilegluglnglugly

65707580

proglutyrtrpaspglygluthrargasnmetlysalaseralagln

859095

thrtyrarggluasnleuargilealaleuargtyrtyrasnglnser

100105110

glualaglyserhisileileglnvalmettyrglycysaspvalgly

115120125

proaspglyargleuleuargglyhisaspglnseralatyraspgly

130135140

lysasptyrilealaleuasngluaspleusersertrpthralaala

145150155160

aspthralaalaglnilethrglnarglystrpglualaalaargval

165170175

alagluglnleuargalatyrleugluglyleucysvalglutrpleu

180185190

argargtyrleugluasnglylysgluthrleuglnargalaasppro

195200205

prolysthrhisvalthrhishisproileserasphisglualathr

210215220

leuargcystrpalaleuglyphetyrproalagluilethrleuthr

225230235240

trpglnargaspglygluaspglnthrglnaspthrgluleuvalglu

245250255

thrargproalaglyaspargthrpheglnlystrpalaalavalval

260265270

valproserglyglugluglnargtyrthrcyshisvalglnhisglu

275280285

glyleuprolysproleuthrleuargtrpgluproserserglnser

290295300

thrvalproilevalglyilevalalaglyleualavalleualaval

305310315320

valvalileglyalavalvalalaalavalmetcysargarglysser

325330335

serglyglylysglyglysertyrserglnalaalacysseraspser

340345350

alaglnglyseraspvalserleuthrala

355360

<210>2

<211>181

<212>prt

<213>homosapiens

<400>2

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>3

<211>181

<212>prt

<213>homosapiens

<400>3

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>4

<211>181

<212>prt

<213>homosapiens

<400>4

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>5

<211>181

<212>prt

<213>homosapiens

<400>5

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>6

<211>181

<212>prt

<213>homosapiens

<400>6

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>7

<211>273

<212>prt

<213>homosapiens

<400>7

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargalaaspproprolysthrhisvalthrhishispro

180185190

ileserasphisglualathrleuargcystrpalaleuglyphetyr

195200205

proalagluilethrleuthrtrpglnargaspglygluaspglnthr

210215220

glnaspthrgluleuvalgluthrargproalaglyaspargthrphe

225230235240

glnlystrpalaalavalvalvalproserglyglugluglnargtyr

245250255

thrcyshisvalglnhisgluglyleuprolysproleuthrleuarg

260265270

trp

<210>8

<211>181

<212>prt

<213>homosapiens

<400>8

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>9

<211>181

<212>prt

<213>homosapiens

<400>9

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>10

<211>181

<212>prt

<213>homosapiens

<400>10

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>11

<211>273

<212>prt

<213>homosapiens

<400>11

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargalaaspproprolysthrhisvalthrhishispro

180185190

ileserasphisglualathrleuargcystrpalaleuglyphetyr

195200205

proalagluilethrleuthrtrpglnargaspglygluaspglnthr

210215220

glnaspthrgluleuvalgluthrargproalaglyaspargthrphe

225230235240

glnlystrpalaalavalvalvalproserglyglugluglnargtyr

245250255

thrcyshisvalglnhisgluglyleuprolysproleuthrleuarg

260265270

trp

<210>12

<211>181

<212>prt

<213>homosapiens

<400>12

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>13

<211>362

<212>prt

<213>homosapiens

<400>13

metargvalthralaproargthrvalleuleuleuleutrpglyala

151015

valalaleuthrgluthrtrpalaglyserhissermetargtyrphe

202530

tyrthralametserargproglyargglygluproargpheileala

354045

valglytyrvalaspaspthrglnphevalargpheaspseraspala

505560

alaserproargmetalaproargalaprotrpilegluglnglugly

65707580

proglutyrtrpaspglygluthrargasnmetlysalaseralagln

859095

thrtyrarggluasnleuargilealaleuargtyrtyrasnglnser

100105110

glualaglyserhisileileglnvalmettyrglycysaspvalgly

115120125

proaspglyargleuleuargglyhisaspglnseralatyraspgly

130135140

lysasptyrilealaleuasngluaspleusersertrpthralaala

145150155160

aspthralaalaglnilethrglnarglystrpglualaalaargval

165170175

alagluglnleuargalatyrleugluglyleucysvalglutrpleu

180185190

argargtyrleugluasnglylysgluthrleuglnargalaasppro

195200205

prolysthrhisvalthrhishisproileserasphisglualathr

210215220

leuargcystrpalaleuglyphetyrproalagluilethrleuthr

225230235240

trpglnargaspglygluaspglnthrglnaspthrgluleuvalglu

245250255

thrargproalaglyaspargthrpheglnlystrpalaalavalval

260265270

valproserglyglugluglnargtyrthrcyshisvalglnhisglu

275280285

glyleuprolysproleuthrleuargtrpgluproserserglnser

290295300

thrvalproilevalglyilevalalaglyleualavalleualaval

305310315320

valvalileglyalavalvalalaalavalmetcysargarglysser

325330335

serglyglylysglyglysertyrserglnalaalacysseraspser

340345350

alaglnglyseraspvalserleuthrala

355360

<210>14

<211>181

<212>prt

<213>homosapiens

<400>14

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>15

<211>181

<212>prt

<213>homosapiens

<400>15

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>16

<211>181

<212>prt

<213>homosapiens

<400>16

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>17

<211>337

<212>prt

<213>homosapiens

<400>17

metargvalthralaproargthrvalleuleuleuleutrpglyala

151015

valalaleuthrgluthrtrpalaglyserhissermetargtyrphe

202530

tyrthralametserargproglyargglygluproargpheileala

354045

valglytyrvalaspaspthrglnphevalargpheaspseraspala

505560

alaserproargmetalaproargalaprotrpilegluglnglugly

65707580

proglutyrtrpaspglygluthrargasnmetlysalaseralagln

859095

thrtyrarggluasnleuargilealaleuargtyrtyrasnglnser

100105110

glualaglyserhisileileglnvalmettyrglycysaspvalgly

115120125

proaspglyargleuleuargglyhisaspglnseralatyraspgly

130135140

lysasptyrilealaleuasngluaspleusersertrpthralaala

145150155160

aspthralaalaglnilethrglnarglystrpglualaalaargval

165170175

alagluglnleuargalatyrleugluglyleucysvalglutrpleu

180185190

argargtyrleugluasnglylysgluthrleuglnargalaasppro

195200205

prolysthrhisvalthrhishisproileserasphisglualathr

210215220

leuargcystrpalaleuglyphetyrproalagluilethrleuthr

225230235240

trpglnargaspglygluaspglnthrglnaspthrgluleuvalglu

245250255

thrargproalaglyaspargthrpheglnlystrpalaalavalval

260265270

valproserglyglugluglnargtyrthrcyshisvalglnhisglu

275280285

glyleuprolysproleuthrleuargtrpgluproserserglnser

290295300

thrvalproilevalglyilevalalaglyleualavalleualaval

305310315320

valvalileglyalavalvalalaalavalmetcysargarglysser

325330335

ser

<210>18

<211>181

<212>prt

<213>homosapiens

<400>18

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>19

<211>298

<212>prt

<213>homosapiens

<400>19

metargvalthralaproargthrvalleuleuleuleutrpglyala

151015

valalaleuthrgluthrtrpalaglyserhissermetargtyrphe

202530

tyrthralametserargproglyargglygluproargpheileala

354045

valglytyrvalaspaspthrglnphevalargpheaspseraspala

505560

alaserproargmetalaproargalaprotrpilegluglnglugly

65707580

proglutyrtrpaspglygluthrargasnmetlysalaseralagln

859095

thrtyrarggluasnleuargilealaleuargtyrtyrasnglnser

100105110

glualaglyserhisileileglnvalmettyrglycysaspvalgly

115120125

proaspglyargleuleuargglyhisaspglnseralatyraspgly

130135140

lysasptyrilealaleuasngluaspleusersertrpthralaala

145150155160

aspthralaalaglnilethrglnarglystrpglualaalaargval

165170175

alagluglnleuargalatyrleugluglyleucysvalglutrpleu

180185190

argargtyrleugluasnglylysgluthrleuglnargalaasppro

195200205

prolysthrhisvalthrhishisproileserasphisglualathr

210215220

leuargcystrpalaleuglyphetyrproalagluilethrleuthr

225230235240

trpglnargaspglygluaspglnthrglnaspthrgluleuvalglu

245250255

thrargproalaglyaspargthrpheglnlystrpalaalavalval

260265270

valproserglyglugluglnargtyrthrcyshisvalglnhisglu

275280285

glyleuprolysproleuthrleuargtrp

290295

<210>20

<211>181

<212>prt

<213>homosapiens

<400>20

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>21

<211>273

<212>prt

<213>homosapiens

<400>21

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargalaaspproprolysthrhisvalthrhishispro

180185190

ileserasphisglualathrleuargcystrpalaleuglyphetyr

195200205

proalagluilethrleuthrtrpglnargaspglygluaspglnthr

210215220

glnaspthrgluleuvalgluthrargproalaglyaspargthrphe

225230235240

glnlystrpalaalavalvalvalproserglyglugluglnargtyr

245250255

thrcyshisvalglnhisgluglyleuprolysproleuthrleuarg

260265270

trp

<210>22

<211>181

<212>prt

<213>homosapiens

<400>22

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>23

<211>362

<212>prt

<213>homosapiens

<400>23

metargvalthralaproargthrvalleuleuleuleutrpglyala

151015

valalaleuthrgluthrtrpalaglyserhissermetargtyrphe

202530

tyrthralametserargproglyargglygluproargpheileala

354045

valglytyrvalaspaspthrglnphevalargpheaspseraspala

505560

alaserproargmetalaproargalaprotrpilegluglnglugly

65707580

proglutyrtrpaspglygluthrargasnmetlysalaseralagln

859095

thrtyrarggluasnleuargilealaleuargtyrtyrasnglnser

100105110

glualaglyserhisileileglnvalmettyrglycysaspvalgly

115120125

proaspglyargleuleuargglyhisasnglntyralatyraspgly

130135140

lysasptyrilealaleuasngluaspleusersertrpthralaala

145150155160

aspthralaalaglnilethrglnarglystrpglualaalaargval

165170175

alagluglnargargalatyrleugluglyleucysvalglutrpleu

180185190

argargtyrleugluasnglylysgluthrleuglnargalaasppro

195200205

prolysthrhisvalthrhishisproileserasphisglualathr

210215220

leuargcystrpalaleuglyphetyrproalagluilethrleuthr

225230235240

trpglnargaspglygluaspglnthrglnaspthrgluleuvalglu

245250255

thrargproalaglyaspargthrpheglnlystrpalaalavalval

260265270

valproserglyglugluglnargtyrthrcyshisvalglnhisglu

275280285

glyleuprolysproleuthrleuargtrpgluproserserglnser

290295300

thrvalproilevalglyilevalalaglyleualavalleualaval

305310315320

valvalileglyalavalvalalaalavalmetcysargarglysser

325330335

serglyglylysglyglysertyrserglnalaalacysseraspser

340345350

alaglnglyseraspvalserleuthrala

355360

<210>24

<211>181

<212>prt

<213>homosapiens

<400>24

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

asnglntyralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnargargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>25

<211>362

<212>prt

<213>homosapiens

<400>25

metargvalthralaproargthrvalleuleuleuleutrpglyala

151015

valalaleuthrgluthrtrpalaglyserhissermetargtyrphe

202530

tyrthralametserargproglyargglygluproargpheileala

354045

valglytyrvalaspaspthrglnphevalargpheaspseraspala

505560

alaserproargmetalaproargalaprotrpilegluglnglugly

65707580

proglutyrtrpaspglygluthrargasnmetlysalaseralagln

859095

thrtyrarggluasnleuargilealaleuargtyrtyrasnglnser

100105110

glualaglyserhisileileglnvalmettyrglycysaspvalgly

115120125

proaspglyargleuleuargglyhisasnglntyralatyraspgly

130135140

lysasptyrilealaleuasngluaspleusersertrpthralaala

145150155160

aspthralaalaglnilethrglnarglystrpglualaalaargval

165170175

alagluglnleuargalatyrleugluglyleucysvalglutrpleu

180185190

argargtyrleugluasnglylysgluthrleuglnargalaasppro

195200205

prolysthrhisvalthrhishisproileserasphisglualathr

210215220

leuargcystrpalaleuglyphetyrproalagluilethrleuthr

225230235240

trpglnargaspglygluaspglnthrglnaspthrgluleuvalglu

245250255

thrargproalaglyaspargthrpheglnlystrpalaalavalval

260265270

valproserglyglugluglnargtyrthrcyshisvalglnhisglu

275280285

glyleuprolysproleuthrleuargtrpgluproserserglnser

290295300

thrvalproilevalglyilevalalaglyleualavalleualaval

305310315320

valvalileglyalavalvalalaalavalmetcysargarglysser

325330335

serglyglylysglyglysertyrserglnalaalacysseraspser

340345350

alaglnglyseraspvalserleuthrala

355360

<210>26

<211>273

<212>prt

<213>homosapiens

<400>26

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

asnglntyralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargalaaspproprolysthrhisvalthrhishispro

180185190

ileserasphisglualathrleuargcystrpalaleuglyphetyr

195200205

proalagluilethrleuthrtrpglnargaspglygluaspglnthr

210215220

glnaspthrgluleuvalgluthrargproalaglyaspargthrphe

225230235240

glnlystrpalaalavalvalvalproserglyglugluglnargtyr

245250255

thrcyshisvalglnhisgluglyleuprolysproleuthrleuarg

260265270

trp

<210>27

<211>273

<212>prt

<213>homosapiens

<400>27

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglytyr

100105110

aspglnaspalatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnargargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargalaaspproprolysthrhisvalthrhishispro

180185190

ileserasphisglualathrleuargcystrpalaleuglyphetyr

195200205

proalagluilethrleuthrtrpglnargaspglygluaspglnthr

210215220

glnaspthrgluleuvalgluthrargproalaglyaspargthrphe

225230235240

glnlystrpalaalavalvalvalproserglyglugluglnargtyr

245250255

thrcyshisvalglnhisgluglyleuprolysproleuthrleuarg

260265270

trp

<210>28

<211>181

<212>prt

<213>homosapiens

<400>28

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglytyr

100105110

aspglnaspalatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnargargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>29

<211>362

<212>prt

<213>homosapiens

<400>29

metargvalthralaproargthrvalleuleuleuleutrpglyala

151015

valalaleuthrgluthrtrpalaglyserhissermetargtyrphe

202530

tyrthralametserargproglyargglygluproargpheileala

354045

valglytyrvalaspaspthrglnphevalargpheaspseraspala

505560

alaserproargmetalaproargalaprotrpilegluglnglugly

65707580

proglutyrtrpaspglygluthrargasnmetlysalaseralagln

859095

thrtyrarggluasnleuargilealaleuargtyrtyrasnglnser

100105110

glualaglyserhisileileglnargmettyrglycysaspleugly

115120125

proaspglyargleuleuargglytyrasnglntyralatyraspgly

130135140

lysasptyrilealaleuasngluaspleusersertrpthralaala

145150155160

aspthralaalaglnilethrglnarglystrpglualaalaargval

165170175

alagluglnargargalatyrleugluglyleucysvalglutrpleu

180185190

argargtyrleugluasnglylysgluthrleuglnargalaasppro

195200205

prolysthrhisvalthrhishisproileserasphisglualathr

210215220

leuargcystrpalaleuglyphetyrproalagluilethrleuthr

225230235240

trpglnargaspglygluaspglnthrglnaspthrgluleuvalglu

245250255

thrargproalaglyaspargthrpheglnlystrpalaalavalval

260265270

valproserglyglugluglnargtyrthrcyshisvalglnhisglu

275280285

glyleuprolysproleuthrleuargtrpgluproserserglnser

290295300

thrvalproilevalglyilevalalaglyleualavalleualaval

305310315320

valvalileglyalavalvalalaalavalmetcysargarglysser

325330335

serglyglylysglyglysertyrserglnalaalacysseraspser

340345350

alaglnglyseraspvalserleuthrala

355360

<210>30

<211>362

<212>prt

<213>homosapiens

<400>30

metargvalthralaproargthrvalleuleuleuleutrpglyala

151015

valalaleuthrgluthrtrpalaglyserhissermetargtyrphe

202530

tyrthralametserargproglyargglygluproargpheileala

354045

valglytyrvalaspaspthrglnphevalargpheaspseraspala

505560

alaserproargmetalaproargalaprotrpilegluglnglugly

65707580

proglutyrtrpaspglygluthrargasnmetlysalaseralagln

859095

thrtyrarggluasnleuargilealaleuargtyrtyrasnglnser

100105110

glualaglyserhisileileglnvalmettyrglycysaspvalgly

115120125

proaspglyargleuleuargglyhisaspglnseralatyraspgly

130135140

lysasptyrilealaleuasngluaspleusersertrpthralaala

145150155160

aspthralaalaglnileileglnarglystrpglualaalaargval

165170175

alagluglnleuargalatyrleugluglyleucysvalglutrpleu

180185190

argargtyrleugluasnglylysgluthrleuglnargalaasppro

195200205

prolysthrhisvalthrhishisproileserasphisglualathr

210215220

leuargcystrpalaleuglyphetyrproalagluilethrleuthr

225230235240

trpglnargaspglygluaspglnthrglnaspthrgluleuvalglu

245250255

thrargproalaglyaspargthrpheglnlystrpalaalavalval

260265270

valproserglyglugluglnargtyrthrcyshisvalglnhisglu

275280285

glyleuprolysproleuthrleuargtrpgluproserserglnser

290295300

thrvalproilevalglyilevalalaglyleualavalleualaval

305310315320

valvalileglyalavalvalalaalavalmetcysargarglysser

325330335

serglyglylysglyglysertyrserglnalaalacysseraspser

340345350

alaglnglyseraspvalserleuthrala

355360

<210>31

<211>181

<212>prt

<213>homosapiens

<400>31

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

asnglntyralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalgluserleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>32

<211>181

<212>prt

<213>homosapiens

<400>32

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuprotyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>33

<211>181

<212>prt

<213>homosapiens

<400>33

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

asnglntyralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargglualagluglnaspargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>34

<211>181

<212>prt

<213>homosapiens

<400>34

serhissermetargtyrphetyrthrservalserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>35

<211>362

<212>prt

<213>homosapiens

<400>35

metargvalthralaproargthrvalleuleuleuleutrpglyala

151015

valalaleuthrgluthrtrpalaglyserhissermetargtyrphe

202530

tyrthralametserargproglyargglygluproargpheileala

354045

valglytyrvalaspaspthrglnphevalargpheaspseraspala

505560

alaserproargmetalaproargalaprotrpilegluglnglugly

65707580

proglutyrtrpaspglygluthrargasnmetlysalaseralagln

859095

thrtyrarggluasnleuargilealaleuargtyrtyrasnglnser

100105110

glualaglyserhisthrleuglntrpmettyrglycysaspvalgly

115120125

proaspglyargleuleuargglyhisaspglnseralatyraspgly

130135140

lysasptyrilealaleuasngluaspleusersertrpthralaala

145150155160

aspthralaalaglnilethrglnarglystrpglualaalaargval

165170175

alagluglnleuargalatyrleugluglyleucysvalglutrpleu

180185190

argargtyrleugluasnglylysgluthrleuglnargalaasppro

195200205

prolysthrhisvalthrhishisproileserasphisglualathr

210215220

leuargcystrpalaleuglyphetyrproalagluilethrleuthr

225230235240

trpglnargaspglygluaspglnthrglnaspthrgluleuvalglu

245250255

thrargproalaglyaspargthrpheglnlystrpalaalavalval

260265270

valproserglyglugluglnargtyrthrcyshisvalglnhisglu

275280285

glyleuprolysproleuthrleuargtrpgluproserserglnser

290295300

thrvalproilevalglyilevalalaglyleualavalleualaval

305310315320

valvalileglyalavalvalalaalavalmetcysargarglysser

325330335

serglyglylysglyglysertyrserglnalaalacysseraspser

340345350

alaglnglyseraspvalserleuthrala

355360

<210>36

<211>181

<212>prt

<213>homosapiens

<400>36

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluserleuargasnleu

65707580

argglytyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

asnglntyralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnargargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>37

<211>181

<212>prt

<213>homosapiens

<400>37

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leuargsertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargglualagluglnargargalatyrleuglu

145150155160

glyglucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>38

<211>181

<212>prt

<213>homosapiens

<400>38

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargarghisleugluasnglylysglu

165170175

thrleuglnargala

180

<210>39

<211>181

<212>prt

<213>homosapiens

<400>39

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargarghisleugluasnglylysglu

165170175

thrleuglnargala

180

<210>40

<211>181

<212>prt

<213>homosapiens

<400>40

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnvallysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>41

<211>181

<212>prt

<213>homosapiens

<400>41

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetgluproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>42

<211>181

<212>prt

<213>homosapiens

<400>42

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

asnglntyralatyraspglylysasptyrileaspleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>43

<211>181

<212>prt

<213>homosapiens

<400>43

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalatyrthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>44

<211>181

<212>prt

<213>homosapiens

<400>44

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnargargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>45

<211>181

<212>prt

<213>homosapiens

<400>45

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglylysthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>46

<211>181

<212>prt

<213>homosapiens

<400>46

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisvalileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>47

<211>181

<212>prt

<213>homosapiens

<400>47

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargglualagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>48

<211>181

<212>prt

<213>homosapiens

<400>48

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluserargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>49

<211>181

<212>prt

<213>homosapiens

<400>49

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnaspargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>50

<211>181

<212>prt

<213>homosapiens

<400>50

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyglucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>51

<211>181

<212>prt

<213>homosapiens

<400>51

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glythrcysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>52

<211>181

<212>prt

<213>homosapiens

<400>52

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluhisleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>53

<211>115

<212>prt

<213>homosapiens

<220>

<221>misc_feature

<222>(115)..(115)

<223>xaacanbeanynaturallyoccurringaminoacid

<400>53

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

asnglnxaa

115

<210>54

<211>362

<212>prt

<213>homosapiens

<400>54

metargvalthralaproargthrvalleuleuleuleutrpglyala

151015

valalaleuthrgluthrtrpalaglyserhissermetargtyrphe

202530

tyrthralametserargproglyargglygluproargpheileala

354045

valglytyrvalaspaspthrglnphevalargpheaspseraspala

505560

alaserproargmetalaproargalaprotrpilegluglnglugly

65707580

proglutyrtrpaspglygluthrargasnmetlysalaseralagln

859095

thrtyrarggluasnleuargilealaleuargtyrtyrasnglnser

100105110

glualaglyserhisileileglnvalmettyrglycysaspvalgly

115120125

proaspglyargleuleuargglyhisaspglnseralatyraspgly

130135140

lysasptyrilealaleuasngluaspleusersertrpthralaala

145150155160

aspthralaalaglnilethrglnarglystrpglualaalaargval

165170175

alagluglnleuargalatyrleugluglyleucysvalglutrpleu

180185190

argargtyrleugluasnglylysgluthrleuglnargalaasppro

195200205

prolysthrhisvalthrhishisproileserasphisglualathr

210215220

leuargcystrpalaleuglyphetyrprovalgluilethrleuthr

225230235240

trpglnargaspglygluaspglnthrglnaspthrgluleuvalglu

245250255

thrargproalaglyaspargthrpheglnlystrpalaalavalval

260265270

valproserglyglugluglnargtyrthrcyshisvalglnhisglu

275280285

glyleuprolysproleuthrleuargtrpgluproserserglnser

290295300

thrvalproilevalglyilevalalaglyleualavalleualaval

305310315320

valvalileglyalavalvalalaalavalmetcysargarglysser

325330335

serglyglylysglyglysertyrserglnalaalacysseraspser

340345350

alaglnglyseraspvalserleuthrala

355360

<210>55

<211>181

<212>prt

<213>homosapiens

<400>55

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargalaalagluglnargargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>56

<211>181

<212>prt

<213>homosapiens

<400>56

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leuargsertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>57

<211>181

<212>prt

<213>homosapiens

<400>57

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglytyr

100105110

hisglnaspalatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>58

<211>108

<212>prt

<213>homosapiens

<400>58

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspgluargleu

100105

<210>59

<211>73

<212>prt

<213>homosapiens

<400>59

leuargglyhisaspglnseralatyraspglylysasptyrileala

151015

leuasngluaspleusersertrpthralaalaaspthralaalagln

202530

ilethrglnarglystrpglualaalaargvalalagluglnleuarg

354045

alatyrleugluglyleucysvalglutrpleuargargtyrleuglu

505560

asnglylysgluthrleuglnargala

6570

<210>60

<211>181

<212>prt

<213>homosapiens

<400>60

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserargargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>61

<211>181

<212>prt

<213>homosapiens

<400>61

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyprolystyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>62

<211>181

<212>prt

<213>homosapiens

<400>62

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

hismetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>63

<211>273

<212>prt

<213>homosapiens

<400>63

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargalaaspproprolysthrhisvalthrhishispro

180185190

ileserasphisglualathrleuargcystrpalaleuglyphetyr

195200205

proalagluilethrleuthrtrpglnargaspglygluaspglnthr

210215220

glnaspthrgluleuvalgluthrargproalaglyaspargthrphe

225230235240

glnlystrpalaalavalvalvalproserglyglugluglnargtyr

245250255

thrcyshisvalglnhisgluglyleuprolyshisleuthrleuarg

260265270

trp

<210>64

<211>181

<212>prt

<213>homosapiens

<400>64

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluthrleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>65

<211>181

<212>prt

<213>homosapiens

<400>65

serhissermetargtyrphehisthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

asnglntyralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>66

<211>181

<212>prt

<213>homosapiens

<400>66

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisasnileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>67

<211>181

<212>prt

<213>homosapiens

<400>67

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglytyr

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>68

<211>181

<212>prt

<213>homosapiens

<400>68

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

asnglntyralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpgluglualaargvalalagluglnargargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>69

<211>181

<212>prt

<213>homosapiens

<400>69

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyprocysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>70

<211>181

<212>prt

<213>homosapiens

<400>70

serhissermetargtyrphetyrthralametserargproglyleu

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>71

<211>181

<212>prt

<213>homosapiens

<400>71

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalathrserproarglysgluproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>72

<211>181

<212>prt

<213>homosapiens

<400>72

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

asnglntyralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalacysvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>73

<211>181

<212>prt

<213>homosapiens

<400>73

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusercystrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>74

<211>273

<212>prt

<213>homosapiens

<400>74

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyproleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargalaaspproprolysthrhisvalthrhishispro

180185190

ileserasphisglualathrleuargcystrpalaleuglyphetyr

195200205

proalagluilethrleuthrtrpglnargaspglygluaspglnthr

210215220

glnaspthrgluleuvalgluthrargproalaglyaspargthrphe

225230235240

glnlystrpalaalavalvalvalproserglyglugluglnargtyr

245250255

thrcyshisvalglnhisgluglyleuprolysproleuthrleuarg

260265270

trp

<210>75

<211>181

<212>prt

<213>homosapiens

<400>75

serhissermetargtyrpheaspthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>76

<211>181

<212>prt

<213>homosapiens

<400>76

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglngly

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>77

<211>181

<212>prt

<213>homosapiens

<400>77

serhissermetargtyrphehisthralametserargproglyarg

151015

glygluproargpheilethrvalglytyrvalaspaspthrleuphe

202530

valargpheaspseraspalathrserproarglysgluproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>78

<211>181

<212>prt

<213>homosapiens

<400>78

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalaserleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>79

<211>181

<212>prt

<213>homosapiens

<400>79

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnserthrtyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>80

<211>181

<212>prt

<213>homosapiens

<400>80

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaasplysalaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>81

<211>273

<212>prt

<213>homosapiens

<400>81

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargalaaspproprolysthrhisvalthrhishispro

180185190

ileserasphisglualathrleuargcystrpalaleuglyphetyr

195200205

proalagluilethrleuthrtrpglnargaspglygluaspglnthr

210215220

glnaspthrlysleuvalgluthrargproalaglyaspargthrphe

225230235240

glnlystrpalaalavalvalvalproserglyglugluglnargtyr

245250255

thrcyshisvalglnhisgluglyleuprolysproleuthrleuarg

260265270

trp

<210>82

<211>181

<212>prt

<213>homosapiens

<400>82

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalahisargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>83

<211>273

<212>prt

<213>homosapiens

<400>83

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

asnglntyralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargglualagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargalaaspproprolysthrhisvalthrhishispro

180185190

ileserasphisglualathrleuargcystrpalaleuglyphetyr

195200205

proalagluilethrleuthrtrpglnargaspglygluaspglnthr

210215220

glnaspthrgluleuvalgluthrargproalaglyaspargthrphe

225230235240

glnlystrpalaalavalvalvalproserglyglugluglnargtyr

245250255

thrcyshisvalglnhisgluglyleuprolysproleuthrleuarg

260265270

trp

<210>84

<211>181

<212>prt

<213>homosapiens

<400>84

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheileservalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>85

<211>273

<212>prt

<213>homosapiens

<400>85

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnileserglnarg

130135140

lysleuglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargalaaspproprolysthrhisvalthrhishispro

180185190

ileserasphisglualathrleuargcystrpalaleuglyphetyr

195200205

proalagluilethrleuthrtrpglnargaspglygluaspglnthr

210215220

glnaspthrgluleuvalgluthrargproalaglyaspargthrphe

225230235240

glnlystrpalaalavalvalvalproserglyglugluglnargtyr

245250255

thrcyshisvalglnhisgluglyleuprolysproleuthrleuarg

260265270

trp

<210>86

<211>181

<212>prt

<213>homosapiens

<400>86

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluserleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>87

<211>181

<212>prt

<213>homosapiens

<400>87

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleugly

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>88

<211>181

<212>prt

<213>homosapiens

<400>88

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglyglulysarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>89

<211>181

<212>prt

<213>homosapiens

<400>89

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

asnglntyralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargglualagluglnargargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>90

<211>181

<212>prt

<213>homosapiens

<400>90

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalacysvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>91

<211>181

<212>prt

<213>homosapiens

<400>91

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualavalargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>92

<211>181

<212>prt

<213>homosapiens

<400>92

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

asnglntyralatyraspglylysasptyrilealaleuasngluasp

115120125

leuserserargthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>93

<211>181

<212>prt

<213>homosapiens

<400>93

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspleuglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>94

<211>181

<212>prt

<213>homosapiens

<400>94

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspleuglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>95

<211>181

<212>prt

<213>homosapiens

<400>95

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrlysarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>96

<211>181

<212>prt

<213>homosapiens

<400>96

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilethrvalglytyrvalaspaspthrleuphe

202530

valargpheaspseraspalathrserproarglysgluproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>97

<211>181

<212>prt

<213>homosapiens

<400>97

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

asnglntyralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglucysleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>98

<211>273

<212>prt

<213>homosapiens

<400>98

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilethrvalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalathrserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargalaaspproprolysthrhisvalthrhishispro

180185190

ileserasphisglualathrleuargcystrpalaleuglyphetyr

195200205

proalagluilethrleuthrtrpglnargaspglygluaspglnthr

210215220

glnaspthrgluleuvalgluthrargproalaglyaspargthrphe

225230235240

glnlystrpalaalavalvalvalproserglyglugluglnargtyr

245250255

thrcyshisvalglnhisgluglyleuprolysproleuthrleuarg

260265270

trp

<210>99

<211>181

<212>prt

<213>homosapiens

<400>99

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalaaspglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>100

<211>181

<212>prt

<213>homosapiens

<400>100

serhissermetargtyrphehisthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>101

<211>181

<212>prt

<213>homosapiens

<400>101

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglysertyrileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>102

<211>181

<212>prt

<213>homosapiens

<400>102

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

thrtrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>103

<211>181

<212>prt

<213>homosapiens

<400>103

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnphealatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>104

<211>181

<212>prt

<213>homosapiens

<400>104

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyleuleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>105

<211>181

<212>prt

<213>homosapiens

<400>105

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaprotrpala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>106

<211>296

<212>prt

<213>homosapiens

<220>

<221>misc_feature

<222>(296)..(296)

<223>xaacanbeanynaturallyoccurringaminoacid

<400>106

metargvalthralaproargthrvalleuleuleuleutrpglyala

151015

valalaleuthrgluthrtrpalaglyserhissermetargtyrphe

202530

tyrthralametserargproglyargglygluproargpheileala

354045

valglytyrvalaspaspthrglnphevalargpheaspseraspala

505560

alaserproargmetalaproargalaprotrpilegluglnglugly

65707580

proglutyrtrpaspglygluthrargasnmetlysalaseralagln

859095

thrtyrarggluasnleuargilealaleuargtyrtyrasnglnser

100105110

glualaglyserhisileileglnvalmettyrglycysaspvalgly

115120125

proaspglyargleuleuargglyhisaspglnseralatyraspgly

130135140

lysasptyrilealaleuasngluaspleusersertrpthralaala

145150155160

aspthralaalaglnilethrglnarglystrpglualaalaargval

165170175

alagluglnleuargalatyrleugluglyleucysvalglutrpleu

180185190

argargtyrleugluasnglylysgluthrleuglnargalaasppro

195200205

prolysthrhisvalthrhishisproileserasphisglualathr

210215220

leuargcystrpalaleuglyphetyrproalagluilethrleuthr

225230235240

trpglnargaspglygluaspglnthrglnaspthrgluleuvalglu

245250255

thrargproalaglyaspargthrpheglnlystrpalaalavalval

260265270

valproserglyglugluglnargtyrthrcyshisvalglnhisglu

275280285

glyleuproasnproserproxaa

290295

<210>107

<211>181

<212>prt

<213>homosapiens

<400>107

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheileservalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpaspglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

asnglntyralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>108

<211>181

<212>prt

<213>homosapiens

<400>108

serhissermetargtyrphetyrthralametserargproglyarg

151015

glygluproargpheilealavalglytyrvalaspaspthrglnphe

202530

valargpheaspseraspalaalaserproargmetalaproargala

354045

protrpilegluglngluglyproglutyrtrpgluglygluthrarg

505560

asnmetlysalaseralaglnthrtyrarggluasnleuargileala

65707580

leuargtyrtyrasnglnserglualaglyserhisileileglnval

859095

mettyrglycysaspvalglyproaspglyargleuleuargglyhis

100105110

aspglnseralatyraspglylysasptyrilealaleuasngluasp

115120125

leusersertrpthralaalaaspthralaalaglnilethrglnarg

130135140

lystrpglualaalaargvalalagluglnleuargalatyrleuglu

145150155160

glyleucysvalglutrpleuargargtyrleugluasnglylysglu

165170175

thrleuglnargala

180

<210>109

<211>362

<212>prt

<213>homosapiens

<400>109

metargvalthralaproargthrvalleuleuleuleutrpglyala

151015

valalaleuthrgluthrtrpalaglyserhissermetargtyrphe

202530

tyrthralametserargproglyargglygluproargpheileala

354045

valglytyrvalaspaspthrglnphevalargpheaspseraspala

505560

alaserproargmetalaproargalaprotrpilegluglnglugly

65707580

proglutyrtrpaspglygluthrargasnmetlysalaseralagln

859095

thrtyrarggluasnleuargilealaleuargtyrtyrasnglnser

100105110

glualaglyserhisthrleuglnargmettyrglycysaspvalgly

115120125

proaspglyargleuleuargglyhisasnglntyralatyraspgly

130135140

lysasptyrilealaleuasngluaspleusersertrpthralaala

145150155160

aspthralaalaglnilethrglnarglystrpglualaalaargval

165170175

alagluglnleuargalatyrleugluglyleucysvalglutrpleu

180185190

argargtyrleugluasnglylysgluthrleuglnargalaasppro

195200205

prolysthrhisvalthrhishisproileserasphisglualathr

210215220

leuargcystrpalaleuglyphetyrproalagluilethrleuthr

225230235240

trpglnargaspglygluaspglnthrglnaspthrgluleuvalglu

245250255

thrargproalaglyaspargthrpheglnlystrpalaalavalval

260265270

valproserglyglugluglnargtyrthrcyshisvalglnhisglu

275280285

glyleuprolysproleuthrleuargtrpgluproserserglnser

290295300

thrvalproilevalglyilevalalaglyleualavalleualaval

305310315320

valvalileglyalavalvalalaalavalmetcysargarglysser

325330335

serglyglylysglyglysertyrserglnalaalacysseraspser

340345350

alaglnglyseraspvalserleuthrala

355360