人源5,10-次甲基四氢叶酸合成酶及其复合物的结晶方法、晶体以及应用的制作方法

专利名称：：人源5,10-次甲基四氢叶酸合成酶及其复合物的结晶方法、晶体以及应用的制作方法
技术领域：
：本发明涉及一种人源5，10-次甲基四氢叶酸合成酶(MTHFS)的晶体及其结晶的方法，同时也涉及人源5，10-次甲基四氢叶酸合成酶与ADP的复合物的晶体及其结晶的方法、人源5，10-次甲基四氢叶酸合成酶与谷氨酸的复合物的晶体及其结晶的方法、人源5，10-次甲基四氢叶酸合成酶与N5-亚胺磷酸过渡态的复合物的晶体及其结晶的方法、人源5，10-次甲基四氢叶酸合成酶与产物10-甲酰四氢叶酸复合物的晶体及其结晶的方法；还涉及这些晶体中对于人源5，10-次甲基四氢叶酸合成酶的酶活性起关键作用的结构域或肽片段；以及利用这些重要结构域或肽片段进行药物设计和筛选的方法。
背景技术：
：叶酸，这种水溶性的B族维生素早在19世纪40年代已被发现。叶酸介导的单碳代谢途径存在于从微生物到高等植物、动物的生命活动中，此代谢途径对细胞的发育和增殖非常重要，并且在很多生理活动中起着非常重要的作用，因此还原型叶酸是其中重要的辅助因子。叶酸只能在原核生物、酵母、植物中合成，但是对人体却是必须的，叶酸介导的单碳代谢途径如果被阻断，在人体内将引发癌症，心血管疾病和发育异常等。该代谢途径中涉及的酶类，很久以来就被用作治疗癌症(A卯ling，1991;FoxandStrover，2008;Chattopadhyayet.al.，2007;Farberet.al.，1948)。目前，抗叶酸药物不仅被用作化疗药物，也在治疗风湿性关节炎和银屑病等疾病中发挥作用。叶酸在生物体内以多种氧化态存在，如叶酸，二氢叶酸，四氢叶酸等。这些不同状态的叶酸携带的单碳单位也存在不同的氧化状态如甲醇或甲酸，它们通过酶学反应进行相互的转换。不同状态的四氢叶酸可以接受或提供单碳单位给多种生命活动。包括(l)嘌呤和嘧啶的从头合成，二磷酸尿嘧啶甲基化形成二磷酸胸腺嘧啶；(2)同型半胱氨酸甲基化形成甲硫氨酸，甲硫氨酸可以形成s-腺苷甲硫氨酸，后者对细胞内的甲基化反应至关重要。嘌呤、嘧啶的从头合成和同型半胱氨酸的合成都对代谢途径上游的合成阻断很敏感，会导致二磷酸尿嘧啶错误地掺入DNA当中，并且会提升细胞内的同型半胱氨酸浓度，破坏s-腺苷甲硫氨酸依赖型甲基化反应。叶酸代谢途径的紊乱将导致多重严重疾病，所以该途径的很多酶都被作为药物设计的重要靶点。叶酸的单谷氨酸衍生物穿过细胞膜进入细胞，在细胞内被多聚谷氨酸合成酶催化合成不同长度的谷氨酸衍生物，多聚谷氨酸支链可以使叶酸存在于细胞内，同时也可以增加其与胞内结合酶类的结合能力。5，10-次甲基四氢叶酸合成酶(Homosapiens5，lO-methenyltetrahydrofolatesynthetase,简称MTHFS)，也称为5_甲酰四氢叶酸环化酶(5-formyltetrahydrofolatecyclo-ligase)。酶学分类号(EC)6.3.3.2.MTHFS催化的体内代谢反应为55-甲酰四氢叶酸5,10-次甲基四氢叶酸反应的底物为5-甲酰四氢叶酸(5-formyltetrahydrofolate，简称5-FTHF)，反应的产物为5，10-次甲基四氢叶酸(5，10-methenyltetrahydrofolate，简称5，10-MTHF)。此催化反应在室温下即可进行，二价镁离子和ATP(三磷酸腺苷)为5，10-次甲基四氢叶酸合成酶的辅助因子。MTHFS存在于很多生物中，包括细菌、植物和动物，表明其在叶酸代谢中具有很重要的作用。目前对叶酸代谢途径中多种重要蛋白的酶学特征研究结果显示，5_甲酰四氢叶酸是目前已知的唯一热动力学稳定的还原型叶酸衍生物，并且没有被直接用作单碳载体。在原核生物中，5_甲酰四氢叶酸被认为是一种单碳载体的储存状态，主要存在于种子和孢子中，其状态随5，10-次甲基四氢叶酸合成酶的表达而变化。在哺乳动物中，5-甲酰四氢叶酸占胞内总叶酸含量的10%-15%，5-甲酰四氢叶酸对一些单碳代谢途径中的酶类有抑制作用，如丝氨酸羟甲基转移酶(serinehydroxymethyltransferase)和5-氨基咪唑_4_甲酰胺基核苷酸转甲酰基酶(AICARTfase)。5，10-次甲基四氢叶酸合成酶是唯一可以将5-甲酰四氢叶酸转换为其它类型还原型叶酸的酶。通过调节体内5-甲酰四氢叶酸的浓度，5，10-次甲基四氢叶酸合成酶可以控制很多叶酸依赖型代谢途径，例如嘌呤、嘧啶、氨基酸等代谢途径。上述代谢途径与生命发育，癌症预防和治疗中的关键步骤紧密相连。有研究表明使用5-甲酰四氢同型叶酸，可以抑制5，10-次甲基四氢叶酸合成酶的活性，进而抑制人乳腺癌。从图1中可以看到，5，10-次甲基四氢叶酸合成酶在单碳代谢途径中的作用，它同时可以正向和反向调节此代谢途径。5，10-次甲基四氢叶酸合成酶是单碳循环上游的关键酶，通过代谢途径的分析，它对下游代谢的影响要比二氢叶酸还原酶显著。对于癌症引起的基因组甲基化异常以及DNA及RNA的完整性、DNA的修复能力等方面来说，5，10-次甲基四氢叶酸合成酶都是一个很关键的调控靶蛋白。5，10-次甲基四氢叶酸合成酶在不同生物中的氨基酸序列与人体内的氨基酸序列同源性比较列于表1中(同源性比较使用NCBI的BLAST软件)表l<table>tableseeoriginaldocumentpage7</column></row><table>虽然原核生物中的5，10-次甲基四氢叶酸合成酶三维结构已经被解析，其与人源5，10-次甲基四氢叶酸合成酶氨基酸序列的同源性仅为28%。而哺乳动物以及人的5，10-次甲基四氢叶酸合成酶的三维结构解析却未见报道。由于叶酸的衍生物在生理环境中不稳定，体内多数叶酸衍生物是以结合在蛋白上的形式存在的。叶酸依赖型单碳代谢网络中酶反应链中存在着底物流传递，即底物与酶结合后发生反应，反应完成后的产物并不与酶分离，而是以这种结合状态传递到下一个酶反应中。研究也表明，这一代谢途径中通过形成中间态来调节酶活性，进而调节代谢途径的趋向和保持动态平衡。如从猪肝中提取的10-甲酰四氢叶酸脱氢酶，就是已结合有带6个谷氨酸的四氢叶酸。这样就导致如果反应链中一个酶发生变异，其中间产物发生积累，则对整个代谢途径的影响都是深远的。MTHFS催化5-甲酰四氢叶酸不可逆转化为5，10-次甲基四氢叶酸(Jolivet，1997)，此催化反应依赖于三磷酸腺苷(adenosine-triphosphate,简称ATP)并且可被产物反馈抑制(Huennekenset.al.，1984;Jolivetet.al.，1996;Maraset.al.，1994)。核磁共振(NMR)波谱和同位素交换方法研究表明MTHFS催化的反应存在两个中间态(HuangandSchirch，1995)。(1)5-甲酰四氢叶酸的甲酰基团亲核攻击ATP的磷酸基团产生第一个N5-亚胺磷酸中间态，这部分反应是可逆的。(2)第二个亲核攻击发生在分子内，N10与N5-亚胺磷酸的N5连接，形成一个四面体中间态磷酸咪唑啉。磷酸咪唑啉中间态移除磷酸基团，最后形成催化产物5，10-次甲基四氢叶酸。5，10-次甲基四氢叶酸是叶酸代谢的中间产物，可以在与酶结合的状态下转化为10-甲酰四氢叶酸。反应的最后一步使得由MTHFS催化的反应不可逆。目前，对这一反应机理的三维结构方面的信息所知甚少。有报道的是源于肺炎支原体(Mycoplasm即皿emoniae)的MTHFS(mpMTHFS)，并且结合二磷酸腺苷(adenonisinedisphosphate，简称ADP)和5-甲酰四氢叶酸的三元复合物结构(Chenet.al.，2005)，另外一个是源于炭疽芽胞杆菌(Bacillusanthracis)(bMTHFS)的MTHFS，并且结合有ADP(Meieret.al.，2007)。人源MTHFS(hMTHFS)的氨基酸序列与蛋白质数据库(http:〃www.rcsb.org/pdb/)中的一级结构相比较同源性少于28%(Bermanet.al.，2000)。从已知的结构看出hMTHFS和mpMTHFS、bMTHFS的整体结构十分相似，预示着MTHFS趋向于一种保守的折叠方式。在鼠类研究中，利用酶稳态动力学和分子模拟技术表明，N5和N10甲基化的叶酸衍生物用做MTHFS抑制物的可行性较小(Fieldet.al.，2006,2007)。在直肠癌和胰癌化疗中常规使用的5-氟尿嘧啶(5-fluorouracil，简称5-FU)是通过抑制胸苷酸合成酶(thymidylatesynthase,简称TS)发挥作用的(Longleyet.al.，2003)，胸苷酸合成酶(TS)从5，10-亚甲基四氢叶酸上获得一个单碳单元来催化脱氧尿苷酸(deoxyuridylate)转化为脱氧胸苷酸(deoxythymidylate)，这一反应对于DNA的合成至关重要(CarrerasandSanti，1995)。临床上，为了提高治疗效果，5-甲酰四氢叶酸(5-formylTHF)通常和5_FU—起使用。这样使用的好处在于MTHFS可以催化5-甲酰四氢叶酸合成5，10-次甲基四氢叶酸，而5，10-次甲基四氢叶酸可以转化为5，10-亚甲基四氢叶酸。低含量的5，10-亚甲基四氢叶酸导致5-FU从TS四聚体上解离下来，从而降低胸苷类似物的抑制效果(Bertino，1977;Sirotnaket.al.，2000)。5，10-亚甲基四氢叶酸也可由丝氨酸羟甲基转移酶(serinehydroxymethyltransferase，简称SHMT)在转化丝氨酸为甘氨酸的过程中合成。SHMT的酶活性可以被MTHFS直接调节，因为MTHFS的底物5-甲酰四氢叶酸可以抑制SHMT(Renwicket.al.，1998;SchirchandSzebenyi，2005;StoverandSchirch，1990)。5-氨基咪唑-4-甲酰胺基核苷酸转甲酰基酶(phosphoribosylaminoimidazolecarboxamidetransformylase,简称AICARFT)和甘氨酰胺核苷酸转甲酰基酶(Glycinamideribonucleotidetransformylase,简称GARFT)是单碳代谢途径中参与嘌呤代谢的两个酶，可以从10-甲酰四氢叶酸上获得单碳单元，也被用来作为抗癌药物的靶点(Allegraet.al.，1985;Piperet.al.，1988)。洛美曲索(Lometrexol)为第二代叶酸拮抗剂的代表，用来抑制GARFT活性，进而抑制嘌呤合成，达到治疗癌症的目地。使用甲氨蝶呤(Methotrexate,简称MTX)和氨基蝶呤(aminopterin)抑制二氢叶酸还原酶(dihydrofolatereductase，简称DHFR)导致二氢叶酸的多聚谷氨酸衍生物积累，进而抑制AICARFT的酶活性(Quinlivanet.al.，2000;Shihet.al.，1997)。同样，通过5-甲酰四氢叶酸的类似物抑制5，10-次甲基四氢叶酸合成酶(5，10-methenyltetrahydrofolatesynthetase,简称MTHFS)导致5_甲酰四氢叶酸的积累，进而抑制丝氨酸羟甲基转移酶(serinehydroxymethyltransferase,简称SHMT)和AICARFT的酶活性。如上所述，酶活性的抑制对碳单元在代谢途径中的转移是有负面效应的，导致细胞中一些重要组分的合成阻断，这也是目前使用叶酸类似物进行癌症化学治疗的机理。使用叶酸衍生物进行癌症治疗，存在两个问题，(一)这些药物经过几十年的使用后，在很多病例中发现了耐药现象，而且对一些病人来说，这两种药物效果不够明显；(二)这些药物多具有比较强的细胞毒性。因此，开发新型叶酸衍生物药物用于癌症化学治疗是目前的研究热点。
发明内容本发明提供一种人源5，10-次甲基四氢叶酸合成酶的晶体，其特征在于所述晶体的空间群为C222l，晶胞参数为a=48.70±2A，b=145.12±2A，c=59.21±2A;a=90.oo°，e=90.oo°，y=90.oo°。本发明提供一种人源5，10-次甲基四氢叶酸合成酶与ADP的复合物的晶体，其特征在于所述晶体的空间群为C2221，晶胞参数为a=48.51±2A,b=145.22±2人，c=59.65±2人；a=90.00°，e=90.00°，y=90.00°。本发明提供一种人源5，10-次甲基四氢叶酸合成酶与ADP的复合物的晶体，其特征在于所述晶体的空间群为P21212，晶胞参数为<formula>formulaseeoriginaldocumentpage9</formula>。本发明提供一种人源5，10-次甲基四氢叶酸合成酶与谷氨酸的复合物的晶体，其特征在于所述晶体的空间群为C2221，晶胞参数为<formula>formulaseeoriginaldocumentpage9</formula>本发明提供一种人源5，10-次甲基四氢叶酸合成酶与N5-亚胺磷酸过渡态的复合物的晶体，其特征在于所述晶体的空间群为C2221，晶胞参数为<formula>formulaseeoriginaldocumentpage9</formula>本发明提供一种人源5，10-次甲基四氢叶酸合成酶与10-甲酰四氢叶酸的复合物的晶体，其特征在于所述晶体的空间群为C2221，晶胞参数为<formula>formulaseeoriginaldocumentpage9</formula>本发明提供一种人源5，10-次甲基四氢叶酸合成酶的晶体的结晶方法，包括将所述人源5，10-次甲基四氢叶酸合成酶的溶液与池液混合；利用悬滴法或坐滴法进行结晶；在l-2天后收集晶体；其特征在于在5至25摄氏度、50%至80%的湿度范围内，池液为含0.01-0.03mol/LMgCl2、0.01-0.04mol/LNiCl2、20%-30%PEG3000至4000、0.lmol/L的pH=6.4-7.0的N-2-羟乙基哌嗪-N-2-乙磺酸或吗啉乙磺酸缓冲液。本发明提供一种人源5，10-次甲基四氢叶酸合成酶与ADP的复合物的晶体的结晶方法，包括向所述人源5，10-次甲基四氢叶酸合成酶的溶液中加入ATP溶液，再加入还原剂和镁离子，混合后得到人源5，10-次甲基四氢叶酸合成酶与ATP的混合液；将所述人源5，10-次甲基四氢叶酸合成酶与ATP的混合液与池液混合；利用悬滴法或坐滴法进行结晶；在1-2天后收集晶体；其特征在于在5至25摄氏度、50%至80%的湿度范围内，池液为含0.01-0.03mol/LMgCl2、0.01-0.04mol/LNiCl2、20%-30%PEG3000至4000、0.lmol/L的pH=6.4-7.0的N-2-羟乙基哌嗪-N-2-乙磺酸或吗啉乙磺酸缓冲液。本发明提供一种人源5，10-次甲基四氢叶酸合成酶与谷氨酸的复合物的晶体的结晶方法，包括向所述人源5，10-次甲基四氢叶酸合成酶的溶液中加入谷氨酸溶液，混合后得到人源5，10-次甲基四氢叶酸合成酶与谷氨酸的混合液；将所述人源5，10-次甲基四氢叶酸合成酶与谷氨酸的混合液与池液混合；利用悬滴法或坐滴法进行结晶；在1-2天后收集晶体；其特征在于在5至25摄氏度、50%至80%的湿度范围内，池液为含0.01-0.03mol/LMgCl2、0.01-0.04mol/LNiCl2、20%-30%PEG3000至4000、0.lmol/L的pH=6.4-7.0的N-2-羟乙基哌嗪-N-2-乙磺酸或吗啉乙磺酸缓冲液。本发明提供一种人源5，10-次甲基四氢叶酸合成酶与N5-亚胺磷酸过渡态的复合物的晶体的结晶方法，包括向所述人源5，10-次甲基四氢叶酸合成酶的溶液中加入ATP、5_甲酰四氢叶酸、巯基乙醇、镁离子溶液，混合后得到人源5，10-次甲基四氢叶酸合成酶与N5-亚胺磷酸的混合液；将所述人源5，10-次甲基四氢叶酸合成酶与N5-亚胺磷酸的混合液与池液混合；利用悬滴法或坐滴法进行结晶；在1-2天后收集晶体；其特征在于在5至25摄氏度、50%至80%的湿度范围内，池液为含0.01-0.03mol/LMgCl2、0.01-0.04mol/LNiCl2、20%-30%PEG3000至4000、0.lmol/L的pH=6.4-7.0的N-2-羟乙基哌嗪_N_2-乙磺酸或吗啉乙磺酸缓冲液。本发明提供一种人源5，10-次甲基四氢叶酸合成酶与10-甲酰四氢叶酸的复合物的晶体的结晶方法，包括向所述人源5，10-次甲基四氢叶酸合成酶的溶液中加入ATP、5_甲酰四氢叶酸、巯基乙醇、镁离子溶液，混合后得到人源5，10-次甲基四氢叶酸合成酶与N5-亚胺磷酸的混合液；将所述人源5，10-次甲基四氢叶酸合成酶与N5-亚胺磷酸的混合液与池液混合；利用悬滴法或坐滴法进行结晶；在4-14天后收集晶体；其特征在于在5至25摄氏度、50%至80%的湿度范围内，池液为含O.01-0.03mol/LMgCl2、0.01-0.04mol/LNiCl2、20%-30%PEG3000至4000、0.lmol/L的pH=6.4-7.0的N-2-羟乙基哌嗪_N_2-乙磺酸或吗啉乙磺酸缓冲液。本发明提供一种人源5，10-次甲基四氢叶酸合成酶的晶体的F55、M58、E61、M90、￥152、￥153位氨基酸在空间中所形成的结构域，其特征在于所述结构域与底物5-甲酰四氢叶酸中的蝶呤基团结合。本发明提供一种人源5，10-次甲基四氢叶酸合成酶的晶体的F85、W109、R148位氨基酸在空间中所形成的结构域，其特征在于所述结构域与底物5-甲酰四氢叶酸中的对氨基苯甲酸基团结合。本发明提供一种人源5，10-次甲基四氢叶酸合成酶的晶体的K10、R14、R145、D154位氨基酸在空间中所形成的结构域，其特征在于所述结构域与ATP结合。本发明提供一种人源5，10-次甲基四氢叶酸合成酶与ADP的复合物的晶体中a5的152-161位氨基酸在空间中所形成的结构域，其特征在于所述结构域是与从ATP水解下来的磷酸基团结合的结构域。本发明提供一种人源5，10-次甲基四氢叶酸合成酶与谷氨酸的复合物的晶体中P3和P4之间的氨基酸即第89和135位氨基酸之间的氨基酸在空间中所形成的结构域，其特征在于所述结构域形成一个loop环结构，该结构中的氨基酸与谷氨酸结合。本发明提供一种人源5，10-次甲基四氢叶酸合成酶与N5-亚胺磷酸过渡态的复合物的晶体中氨基酸残基F55，L56，S57，M58，E61，P81，Y83，M90，W109，P135，R148，K150，Y152和Y153所形成的结构域，其特征在于所述结构域形成一个球形口袋，N5-亚胺磷酸过渡态的蝶呤环位于所述球形口袋的中间。本发明提供一种人源5，10-次甲基四氢叶酸合成酶与N5-亚胺磷酸过渡态的复合物的晶体中蝶呤环在空间中的结构域，其特征在于所述蝶呤环以C4a与C8a之间的键为轴发生了扭转，所述喋呤环上的电子发生了重排。本发明提供一种人源5，10-次甲基四氢叶酸合成酶与10-甲酰四氢叶酸的复合物的晶体中Y83在空间中的结构域，其特征在于Y83的位置与在权利要求5所述的晶体的位置相比，发生了变化。本发明提供与上述的任一结构域类似或者结合的小分子化合物、短肽、多肽、核酸、抗体或免疫结合物中的一种或几种的组合物。图1示出了5，10-亚甲基四氢叶酸合成酶在单碳代谢途径中的位置及作用。TS:胸苷酸合成酶(thymidylatesynthase,简称TS);MTHFS:5，10-次甲基四氢叶酸合成酶(5，10-methenyltetrahydrofolatesynthetase，简称MTHFS);SHMT:丝氨酸羟甲基转移酶(serinehydroxymethyrltransferase，简称SHMT);DHFR:二氢口十酸还原酶(dihydrofolatereductase,简称DHFR);MTHFR:亚甲基四氢叶酸还原酶(Methylenetetrahydrofolatereductase,简称MTHFR);MTHFD:亚甲基四氢叶酸脱氢酶(methylenetetrahydrofolatedehydrogenase,简称MTHFD)图2示出了MTHFS催化反应产物5，10-次甲基四氢叶酸转化为10-甲酰四氢叶酸，5，10-次甲基四氢叶酸是叶酸代谢的中间产物，可以在与酶结合状态转化为10-甲酰四氢叶酸。A:5，10-次甲基四氢叶酸；B:10-甲酰四氢叶酸。图3示出了5，10-亚甲基四氢叶酸合成酶晶体的立体三维结构示意图。图4示出了5，10-亚甲基四氢叶酸合成酶与ADP的复合物的晶体的三维结构示意图。图5示出了5，10-亚甲基四氢叶酸合成酶与谷氨酸的复合物的晶体的三维结构示意图。图6示出了5，10-亚甲基四氢叶酸合成酶与N5-亚胺磷酸过渡态的复合物的晶体的三维结构示意图。图7示出了5，10-亚甲基四氢叶酸合成酶与10-甲酰四氢叶酸的复合物的晶体的三维结构示意图。具体实施例方式人源5，10-次甲基四氢叶酸合成酶(MTHFS)的表达与纯化MTHFS的氨基酸序列如下MAAAAVSSAKRSLRGELKQRLRAMSAEERLRQSRVLSQKVIAHSEYSTA从商品化人转录文库中PCR克隆得到全长的人MTHFS的基因。使用的引物如下BCO19921上游TACTTCCAATCCAATGCTATGGCGGCGGCAGCGGTBC019921下游TTATCCACTTCCAATGTTAAGCTGTTGACGAGTCT克隆得到的基因，通过连接反应克隆到商品化PET2lb载体中，该载体在蛋白质的氮端具有6个组氨酸的表达标签。使用BL21(DE3)宿主菌表达重组蛋白，37摄氏度，当菌浓度达到0D6。Qnm=0.8时，加入终浓度为0.2mM的IPTG。然后，16摄氏度表达24小时，4000rpm，收集表达菌。收集的表达菌重悬于磷酸盐缓冲液(50mMNa2HP04，10mMKH2P04，137mMNaCl，2.7mMKC1，pH7.4)，使用100W超声波破碎细胞，在磷酸盐缓冲液中重悬细菌，16000rpm，30分钟，取上清，经QIAGEN的Ni-NTA亲和层析柱可以得到初步纯化的蛋白，使用烟草蚀纹病毒(TEV)蛋白酶切除酶氮端具有的6个组氨酸表达标签。然后，再通过QIAGEN的Ni-NTA亲和层析柱去除蛋白中的TEV蛋白酶及6个组氨酸表达标签。获得的纯化蛋白，使用Milipore公司的浓縮产品Amicon、截留分子量为5kDa，浓縮蛋白到1毫升，使用GE公司的SuperDexG75分子筛纯化。使用分子筛纯化MTHFS为单一的洗出峰，同时蛋白缓冲液换为20mMTris-HCl，pH8.0，200mMNaCl，0.5mMEDTA(乙二胺四乙酸二钠)和5mMP-巯基乙醇-merc即toethanol)，使用Milipore公司的浓縮产品Amicon，截留分子量为5kDa，浓縮至lj10mg/ml。晶体的生长晶体可采用分批结晶、液-液扩散、蒸气扩散、透析等方法获得。本发明中采用的是液_液扩散的方法，包括悬滴法或坐滴法。在以下的实验中采用Hampton公司的晶体筛选试剂盒，晶体生长的条件为在5至25摄氏度、50%至80%的湿度范围内，池液为含0.01-0.03mol/LMgCl2、0.01-0.04mol/LNiCl2、20%-30%PEG3000至4000、0.lmol/L的pH=6.4-7.0的N-2-羟乙基哌嗪-N-2-乙磺酸或吗啉乙磺酸缓冲液。在结晶前，将人源5，10-次甲基四氢叶酸合成酶与池液混合或者将人源5，10-次甲基四氢叶酸合成酶和各种底物的混合液与池液混合。下面披露一些优选的实施方式人源5，10-次甲基四氢叶酸合成酶的晶体的结晶方法，首先将所述人源5，10-次甲基四氢叶酸合成酶的浓縮液与池液混合；将上述酶蛋白溶液在Eppendorf冷冻离心机离心14，OOOrprn，15分钟；采用Hampton公司的晶体筛选试剂盒结晶，结晶的池液的组成为0.02MMgCl2、0.02MNiCl2、HEPES(O.1M，p朋.6)和20%PEG3350，大约两天后收集得到的晶体。人源5，10-次甲基四氢叶酸合成酶与ADP的复合物的晶体的结晶方法，首先向所述人源5，10-次甲基四氢叶酸合成酶的溶液加入终浓度为5mM的ATP溶液，再加入还原剂和镁离子，混合后得到人源5，10-次甲基四氢叶酸合成酶与ATP的混合液；将所述人源5，10-次甲基四氢叶酸合成酶与ATP的混合液与池液混合1小时；结晶前将所述蛋白溶液在E卯endorf冷冻离心机离心14，OOOrprn，15分钟(主要目的是为了去除杂质)，采用Hampton公司的晶体筛选试剂盒结晶，结晶的池液的组成为O.02MMgCl2、0.02MNiCl2、HEPES(0.1M，p朋.6)和20%PEG3350,1_2天收集晶体进行数据收集。人源5，10-次甲基四氢叶酸合成酶与谷氨酸的复合物的晶体的结晶方法，向5-10mg/ml蛋白溶液中加入终浓度为3mM的谷氨酸溶液，混合1小时，结晶前将所述蛋白溶液在E卯endorf冷冻离心机离心14，OOOrpm，15分钟，采用Hampton公司的晶体筛选试剂盒结晶，结晶的池液的组成为0.02MMgCl2、0.02MNiCl2、HEPES(O.1M，p朋.6)和20%PEG3350,1-2天收集晶体进行数据收集。人源5，10-次甲基四氢叶酸合成酶与N5-亚胺磷酸过渡态的复合物的晶体的结晶方法，向5-10mg/ml蛋白溶液中加入终浓度为5mMATP、5mM5-甲酰四氢叶酸、2mM巯基乙醇、5mM镁离子，混合1小时，结晶前将所述蛋白溶液在Eppendorf冷冻离心机离心14，000rpm，15分钟，采用Hampton公司的晶体筛选试剂盒结晶，结晶的池液的组成为0.02MMgCl2、0.02MNiCl2、HEPES(0.1M，p朋.6)和20%PEG3350,1-2天收集晶体进行数据收集。人源5，10-次甲基四氢叶酸合成酶与10-甲酰四氢叶酸的复合物的晶体的结晶方法，5-10mg/ml蛋白溶液中加入终浓度为5mMATP、5mM5-甲酰四氢叶酸、2mM巯基乙醇、5mM镁离子，混合1小时，结晶前将所述蛋白溶液在E卯endorf冷冻离心机离心14，OOOrpm，15分钟，结晶的池液的组成为0.02MMgCl2、0.02MNiCl2、HEPES(O.1M，p朋.6)和20%PEG3350，4-14天收集晶体进行数据收集。结晶的具体过程为晶体生长于16t:，进行悬滴蒸气扩散结晶或坐滴法结晶实验，将包含混合池液2微升和2微升蛋白溶液或蛋白溶液与底物或产物的混合液的混合，进行扩散，在300iil包含O.02MMgCl2、0.02MNiCl2、HEPES(0.lM，p朋.6)和20%PEG3350的池液存在下，经过一段时间发现最大尺寸达300-500i！m的片状晶体，将晶体转移至包含0.01MMgC12、0.01MNiC12、HEPES(0.lM，p朋.6)、10%PEG3350、20X甘油作为防冻剂的溶液中。然后在收集X-射线数据前快速冷冻样品。晶体的解析获得的复合物晶体转移到含有10_15%甘油的池液中，挑出单晶，快速冷冻至液氮中，经初步X衍射筛选后，确定要收集的晶体数据。衍射数据的收集使用同步辐射，波长为0.979A，数据初步处理使用HKL2000(0twinowskiandMinor,1997)。野生型结构解析使用分子置换方法，使用软件为Balbes(Longet.al.，2008)，以蛋白质数据库中的mpMTHFS(PDBcode1U3G)建模。复合物晶体数据收集使用in-houseFRE+copperrotatinganodeandaR-AXISIV++detector(Rigaku，USA)及同步辐射。复合物结构的解析使用软件为Phaser(McCoyet.al.，2007)，以人源hMTHFS的结构为模板建模。结构模型的修正使用软件Phenixrefine(Adamset.al.，2002)和Refmac(Murshudovet.al.，1997)。用R因子和Rfree因子来监测模型质量和修正误差。人源5，10-次甲基四氢叶酸合成酶的晶体，空间群为C2221，晶胞参数为a=48.70±2A,b=145.12±2A，c=59.21±2A;a=90.00°，P=90.00°，y=90.00°。人源5，10-次甲基四氢叶酸合成酶与ADP的复合物的晶体，空间群为C2221，晶胞参数为a=48.51±2A，b=145.22±2A,c=59.65±2A;a=90.00°，e=90.00°，y=90.00°。人源5，10-次甲基四氢叶酸合成酶与ADP的复合物的晶体，空间群为P21212，晶胞参数为a=59.579±2A,b=144.101±2A,c=48.532±2A;a=90.00°，P=90.00°，y=90.00°。人源5，10-次甲基四氢叶酸合成酶与谷氨酸的复合物的晶体，空间群为C2221，晶胞参数为a=48.45±2A,b=145.23±2A,c=59.60±2A;a=90.00°，e=90.00°，y=90.00°。人源5，10-次甲基四氢叶酸合成酶与N5-亚胺磷酸过渡态的复合物的晶体，空间群为C222l，晶胞参数为a=48.69±2A,b=141.03±2A,c=59.99±2A;a=90.00°，P=90.00°，y=90.00°。人源5，10-次甲基四氢叶酸合成酶与10-甲酰四氢叶酸的复合物的晶体，空间群为C222l，晶胞参数为a=48.86土2A,b=144.97±2A,c=59.41±2A;a=90.00°，P=90.00°，y=90.00°。表2为人源5，10-次甲基四氢叶酸合成酶的晶体的坐标表2<table>tableseeoriginaldocumentpage14</column></row><table>48NALAA935.63352.207-7.26210029.5949CAALAA935.24451.141-6.34910019.0350CBALAA935.76851.432—4.95510027.2851CALAA933.72751.002-6.33410023.14520ALAA933.19449.897-6.42810029.0753NLYSA1033.03952.134-6.23610022.0754CALYSA1031.58052.146-6.21210025.8855CBLYSA1031.05153.566-5.97010032.8656CGLYSA1031.32954.113_4.57310022.9957CDLYSA1030.75155.518-4.39910021.0258CELYSA1030.61655.880-2.92510032.3659NZLYSA1029.96657.207-2.72610043.9660CLYSA1030.99751.578-7.50310025.13610LYSA1030.08550.750-7.47410025.5662NARGA1131.53152.024-8.6361.0023.0963CAARGA1131.06551.553-9.9301.0020.]764CBARGA1131.81752.271-ll.0511.0033.5065CGARGA1131.44651.815-12.4461.0032.4366CDARGA1132.30652.533-13.4741.0037.1267NEARGA1133.71252.514-13.0801.0035.8368CZARGA1134.51651.468-13.2401.0046.9269NH1ARGA1134.05550.354-13.7941.0047.6970NH2ARGA1135.78251.534-12.8481.0043.7971CARGA1131.22950.045-IO.0731.0021.69720ARGA1130.32549.355-IO.5431.0024.1773NSERA1232.38449.531_9.6631.0030.4874CASERA1232.63348.095-9.7501.0038.2975CBSERA1234.07147.762-9.3481.0033.8776OGSERA1234.98948.210-IO.3301.0035.6077CSERA1231.65147.328_8.8761.0033.45780SERA1231.07146.328-9.3041.0035.5679NLEUA1331.46447.805-7.6501.0028.3580CALEUA13SO-55247.153_6.7221.0026.8081CBLEUA13SO.62747.801-5.3401.0026.1782CG固A1329.80347.135-4.2341.0031:2583CD1LEUA13SO-01345.617一4.2181.0027.4584CD2腦A13SO.14747.739-2.8911.0026.7185CLEUA1329.11947.151_7.2541.0025.78860LEUA1328.41446.148-7.1431.0030.5887NARGA1428.69048.268-7.8361.0025.5388CAARGA1427.36948.333-8.4561.0030.1789CBARGA1427.12249.707-9.0841.0022.6590CGARGA1426.97850.830-8.0751.0022.4491CDARGA1426.46852.114-8.71410027.0292NEARGA1426.45653.198_7.73810027.2693CZARGA1427.29554.227-7.7431.0034.4094NH1ARGA1428.21154.341-8.6991.0031.5095NH2ARGA1427.20955.147_6.7941.0032.5296CARGA1427.22447.248-9.51710031.22970ARGA1426.17746.604_9.62510028.0098NGLYA1528.28047.050-10.2991.0030.5999CAGLYA1528.28046.021-11.32310039.04100CGLYA1528.16844.643-IO.70610041.451010GLYA1527.37043.815-11.14310042.15102NGLUA1628.97144.402-9.67710036.59103CAGLUA1628.93743.136_8.95710044.44104CBGLUA1630.04943.088-7.9031.0040.98105CGGLUA1631.43243.454一8.44110052.74NCCc0NcccccNc0NccccNcNNC0IScc0c0Ncccccc0NccccNcNNC0NCC0Nccc子子子子子子于子子于于子子子子子原原原原原原-:—-—15106CDGLUA1632.51343.427_7.3731.0068.63107OE1GLUA1632.50242.500-6.5351.0061,94108OE2GLUA1633.37944.329-7.3741.0067.31109CGLUA1627.56942.908-8.3131.0040.081100GLUA1627.07141.786-8.2851.0051.08111N固A1726.96343.982-7.8131.0043.70112CALEUA1725.67243.905-7.1281.0040.38113CBLEUA1725.42245.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8633.04559.355-2.6331.0056.300原子1462匿ASNA18631.01960.282-2.9171.0064.85N原子14630ASNA18632.32759.7622.4551.0059.600原子14640ALAA19024.51157.2054.4861.0040.410原子1465NALAA19026.13959.4193.7411.0046.14N原子1466CAALAA19025.48359.3315.0431.0038.96c原子1467CALAA19025.04457.8985.3511.0033.11c原子1468CBALAA19024.29760.2815.1031.0045.44c原子1469NLYSA19125.27757.4536.5811.0032.25N原子1470CALYSA19124.89856.1026.9741.0033.05c原子1471CBLYSA19125.71755.6318.1731.0039.21c原子1472CGLYSA19127.22055.7058.0101.0037.53c原子1473CDLYSA19127.86754.6938.9371.0043.35c原子1474CELYSA19129.12155.2349.5911.0046.63c原子1475NZLYSA19129.49454.40710.7741.0057.53N原子1476CLYSA19123.42256.0197.3321.0034.18c原子14770LYSA19122.83656.9897.81010035.970原子1478NVALA19222.82854.8537.1051.0027.06N原子1479CAVALA19221.柳54.5947.5611.0024.39c原子1480CBVALA19220.72353.6036.6431.0023.86c原子1481CGIVALA19220.59954.1765.23410025.04c原子1482CG2VALA19221.42852.2586.60810025.90c原子1483CVALA19221.52954.0548.98010031.85c原子14840VALA19222.54353.4919.39510031.640原子1485NASPA19320.44854.2349.72910024.62N原子1486CAASPA19320.43053.81111.12210026.41c原子1487CBASPA19319.20954.37811.83710020.49c原子1488CGASPA19319.36255.84912.15510022.17c原子1489OD1ASPA19320.41456.22412.71310036.450原子1490OD2ASPA19318.43256.62511.85510021.620原子1491CASPA19320.44152.30311.23310025.18c原子14920ASPA19321.08351.73812,12010022.990原子1493NGLUA19419.73051.65310.32110022.26N原子1494CAGLUA19419.56850.21310.39210019.27c原子1495CBGLUA19418.42649.88211.34510029.48c原子1496CGGLUA19418.13348.41111.50610022.64c原子1497CDGUJA1947.17348.16512.6540025.10c0E1GLUA19416.85846.9911293410037.980原子14990E2GLJA19416.74049.1601327310034.350原子1500CGLUA19419.30049.604902710023.05C原子15010GLUA19418.55550.161821710018.310原子1502NVALA19519.91948.456878110021.02N原子1503CAVALA19519.66547.699756510027.72C原子1504CBVALA19520.97247.377680310023.14c原子1505CGIVALA19521.81648.627663710024.03c原子1506CG2VA匕A19521.76646.3007.52410052.71c原子1507CVALA19518.95046.4067.94310028.09c原子15080VAI.A19519.42245.6598.79410025.890原子1509NLEUA19617.79546.1627.33510017.17N原子1510CALEUA19617.04944.9407.58510021.85c原子1511CBLEUA19615.55845.2367.74010023.73c原子1512CGLEUA19615.14546.0978.93610025.55c原子1513CD1LEUA19613.62946.2428.96710021.28c原子1514CD2LEUA19615.65745.48410.22410022.11c原子1515CLEUA19617.25143.9796.4311.0028.50c原子15160LEUA19617.35844.3975.2781.0020.600原子1517NTYRA19717.29042.6906.7461.0023.79N原子1518CATYRA19717.45941.6615.7331.0023.77c原子1519CBTYRA19718.82041.8125.0631.0017.47c原子1520CGTYRA19719.97541.6126.0151.0022.60c原子1521CD1TYRA19720.52240.3516.2151.0033.83c原子1522CE1TYRA19721.57340.1597.0881.0028.87c原子1523CZTYRA19722.09241.2327.7791.0032.8'6c原子1524OHTYRA19723.14141.0408.6491.0037.850原子1525CE2TYRA19721.56742.4967.6001.0038.33c原子1526CD2TYRA19720.51342.6796.7221.0031.81c原子1527CTYRA19717.38240.2916.3791.0020.89c原子15280TYRA19717.72240.1387.5541,0032.650原子1529NGLUA19816.92639.3025.6141.0031.22N原子1530CAGLUA19817.09237.8995.9951.0029.71c原子1531CBGLUA19816.62837.6357.4281.0052.28c原子1532CGGLUA19817.49236.6138.1561.0053.70c原子1533CDGLUA19818.98336.8878.0051.0050.28c原子1534OE1GLUA19819.43337.2106.8821.0045.720原子1535OE2GLUA19819.71236.7689.0121.0063.900原子1536CGLUA19816.44836.9215.01810037.74c原子15370GLUA19815.66337.3154.15510042.790原子15380ALAA19914.19033.7614.58410043.850原子1539NALAA19916.80335.6465.15510045.01N原子1540CAALAA19916.38134.6234.20410037.79c原子1541CALAA19914.87334.6194.0321.0042.44c原子1542CBALAA19916.86433.2474.65110056.16c原子15430HOH19.58367.0671.0991004.200原子15440HOH29.96270.0550.51110016.460原子15450HOH38.03057.515-6.47310019.940原子15460HOH411.74656.5610.95910015.980原子15470HOH50.92854.112-1147610017.610原子15480HOH69.52755.580-525710019.760原子15490■79.17472.967-2.61810020.160原子15500匪8-O.14262.909-10.97110019.760原子15510HOH90.83154.30913.61210023.810原子15520HOH1011.04671.372-2.86210013.360原子15530HOH1116.15646.268-l.68810021.530原子15540HOH1223.34157.589-5.00710027.920原子15550國1311.29442.957一640310032.980原子15560H0H140.00054.788-14.8041.0029.190原子15570HOH153.50666.394-8.2401.0024.860原子15580HOH166,01249.126-4.1181.0026.620原子15590HOH1710.08666.627-7.2991.0023.300原子15600HOH1813.64272.4632.34610031.110原子15610HOH190.36266.4017.18010025.870原子15620■204.皿70.052-4.88010024.350原子15630■21-5.03755.9227.05010034.820原子15640■2212.23652.918-5.74610029.850原子15650HOH2318.67159.07012.36910043.000原子15660HOH241.31546.97716.5781.0035.890原子15670HOH25-3.19757.7666.9771.0029.530原子15680■2610.38969.271-7.1571.0017.050原子15690HOH2725.52757.1340.0971.0035.690原子15700HOH280.05945.27511.3521.0028.910原子15710■2911.37657.034-IO.6541.0022.350原子15720HOH306.40545.0941.5801.0026.760原子15730■31-3.83162.752-2.9311.0032.780原子15740■3211.14160.326-16.0701.0026.740原子15750HOH336.73572.5610.0000.7711.810原子15760HOH349.53058.150-8.8051.0022.020原子15770HOH3516.42739.8862.9761.0028.660原子15780HOH360.13848.701-1.2621.0027.300原子15790匪371.46451.70214.6031.0024.790原子15800HOH3831.31242.328-O.5521.0032.800原子15810HOH3912.36446.39717.0671.0035.330原子15820HOH403.70849.731-4.7601.0026.440原子15830HOH413.53371.268-0.3361.0027.240原子15840丽426.76364.585-11.5571.0030.920原子15850HOH43-8.41956.456-2.3701.0029.900原子15860HOH442.07472.3362.7231.0031.620原子15870HOH4513.20630.466-7.2491.0033.580原子15880HOH467.43967.126-11.0721.0036.310原子15890HOH475.49761.144-13.2581.0030.700原子15900■48-0.86344.6147.4041.0031.320原子15910HOH496.41749.742-8.2871.0033.540原子15920HOH5016.43659.82914.9531.0035.850原子15930■519.81266.574-10.1761.0027.700原子15940國52-7.88064.6261.8741.0056.140原子15950■5316.30948.928_1.7401.0031.700原子15960HOH5432.31044.685—0.23310036.380原子15970■557.59064.45912.11210032.700原子15980■567.91070.302_8.30610034.010原子15990HOH5718.21440.463-9.56310028.630原子16000■5819.49339.98910.35110045.090原子16010HOH5911.71043.47713.55910031.770原子16020HOH6012.29955.406-6.24110032.820原子16030HOH61-6.74166.7160.52810042.370原子16040國628.50070.7118.24710026.350原子16050■636.67059.62117.45510048.640原子16060HOH6431.04356.Oil-9.09610039.000原子16070HOH6520.16058.4589.25510044.830原子16080■669.81864.20413.6520044.890原子16090HOH67-1.06259.8313.96910020.690原子16100■6818.89338.320-11.92510035.040原子16110HOH6929.34358.240-O.09710042.870原子16120■7017.10665.358_3.01510024.460原子16130HOH7110.46570.738-15.25710043.180表3为人源5，10-次甲基四氢叶酸合成酶与谷氨酸的复合物的晶体的坐标:表316140H0H7229.56958.034-7.5051.0039..6516150HOH73-3.44859.6844.9981.0034.6216160HOH745.54743.502-0.6211.0037.0616170HOH751.03249.483-3.6531.0040.5116180HOH764.88859.84820,5261.0035.5716190HOH7718.00742.0469.9191.0036.2216200HOH7833.48060.828-10.0121.0044.1516210HOH7927.71960.1961.6171.0038.5116220HOH8027.60041.102-2.1951.0041.8916230■8122.00647.62910.8671.0034.2716240HOH8218.46633.821-2.1191.0038.1216250HOH8320.98636.410-10.9281.0041.1316260HOH8414.09530.178-1.7621.0038.0216270HOH85-2.57867.1241.8611.0037.0316280■8619.97858.288_3.9841.0020.0616290關87-6.57654.9272.6011.0039.5716300腳8817.17230.892-O.5141.0043.6816310HOH89_6.78163.9604.2841.0045.1816320HOH905.59041.3301.1441.0036.0416330■9110.58869.78213.6441.0056.5616340HOH9234.93847.666-5.2521.0038.6316350HOH9328.13553.804-1.5721.0042.146360關9423.82349.73711.3921.0054.1616370HOH9510.32039.781-11.2631.0049.6916380HOH9619.88443.016-7.1881.0052.4616390HOH9711.17426.833-8.0581.0049.8616400■9816.77057.623一9.6081.0042.9416410HOH99-2.27266.7328.1721.0059.6916420HOH10019.43544.20810.8741.0038.3216430關10117.53330.4192.4701.0047.4816440HOH1024,39941.716—2.6471.0042.210000000000000000000000000000000子子子子0035.43N0041.41C0045.63C0045.32c0037.59c0059.03s0053.80c0042.0900049.5300048.40N0045.74c0049.29c0040.17c0042.9000048.58N0052.51c0050.38c0047,96c0036.70N0040.63c0032.11c0039.83c0035.2300029.09N0031.34c0040.09c0041.10c0035.6800038.33N0048.93c0060.52c0047.51c0034.39c0031.98c0028.6800042.71N0034.73c0035.76c0051.4600040.44c0039,3500034.96N0035.73c0030.41c0041.6800040.24c0031.0400027.74N0028.91c0036.07c0030.07c0036.1700032.46N0040.86c0041.64c0038.00c0034.36c0032.98cCN101781637A说明书A1-17348-10.1837.583A1-17.905-11.5157.788A1-17380-12.4766.724A1-19.440-11.4787.773A1一20.067-10.6178.868A1-19.725-11.22810.533A1-20.654-12.75710.528A1-16.773-13.4997.044A2-14.960-14.0264.128A2-17.615-12.1385.458A2-17.077-12.9054.338A2-15.560-13.0014.459A2-17.464-12.2573.017A3-12.247-13.6806.175A3-14.950-11.9174.932A3-13.517-11.8815.196A3-13.159-12.8596.315A3-13.085-10.4665.567A4-13.885-12.759了，425A4-13.661-13.6208.579A4-14.641-13.2859.702A4-13.771-15.0868.195A4-12.959-15.9058.628A5-14.778-15.4097.385A5-14.978—16.7766.915A5-16.217-16.8656.040A5-13.748-17.2656.160A5-13.344-18.4266.293A6-13.156-16.3765.366A6-ll.916-16.6874.663A6-ll.498-15.5463.698A6-10.167-15.8603.028A6-12.570-15.3192.641A6-10.802—16.9825.672A6-IO.124-18.0125.576A了-10.639-16.0876.647A了—9.637-16.2507.703A7—9.676-15.0748.687A7-9.444-13.8378.036A7-9,805-17.5658.462A7—8.821-18.2368.781A8-ll.049-17.9278.762A8-11.317-19.1989.426A8-12.805-19.3599.732A8-13.055-20.64910.259A8-10.831-20.3688.572A8-10.080-21.2269.046A9-11.255-20.3927.311A9-10.852-21.4536.390A9-11.508-21.2645.032A9-9.325-21.5466.257A9-8.765-22.6406.218A10_8.652-20.4006.195A10-7.191-20.3876.172A10_6.657-18.9645.966A10一6.842-18.4154.561A10一6293-16.9974.444A10一6.150—16.5922.9801N2CA3C4CB5CG6SD7CE809010N11CA12C13CB14015N16CA17C18CB19N20CA21CB22C23024N25CA26CB27C28029N30CA31CB32CG133CG234C35036N37CA38CB39OG40C41042N43CA44CB45OG46C47048N49CA50CB51C52053N54CA55CB56CG57CD58CE別^则M賜加加M:MIMMMM;MMMMMMMMMMMMMMMMMMM:M:MIMMMM制MM服M加别加服^加^加^服^加^W^ooooooooooooooooooooooooooooooooooooocuooooooooooooooooooooTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT丁TTTTTTTAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAATTTTTAAAAAAAAAAAAAAAAAAAA!IJlI.LIJIJII"ILRRRRRRRRRRiRRAAAAASSSSSSMMMMMAAAAAAAAAAAAAAAAAAAAVVVVVVVSSSSSSSSSSSSAAAAALLLLLL10-5.606-15.2162.82910055.5010-6.622-20.9737.46110038.4510-5.691-21.7807.43010038.5011-7.184-20.5508.59110033.3911-6.722-20.9999.90110029.6911-7.484-20.26511.00710057.9511-7.17920.74312.■42210054.2611-8.149-20.14113.43710056.6811-9.533-20.18712.96710057.1211-10.333-21.24313.08110059.0011-9.894-22.35713.65310052.9711-11.576-21.18912.62110057.1111-6.850-22,51410.06710039.3911-5.913-23.18110.51110038.2212-8.004-23.0639.7041.0032.8012-8.183-24.5079.7741.0035.8812-9.612-24.9059.3991.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0.981565NINIC1—9.273—26.086-8.2571.0060.901566NINIC213.510-2.3325.2781.003S/071567MGMGD114.614-5.513-1.0771.0014.361568MGMGE1-6.266-30.6920.6221.0048.451569MGMGF14.519-14.8114.8331.0043.681570MGMGG18.965-15.7189.6651.0051.1415710HOHS120.670-6.1978.1031.0020.5015720HOHS223.088-18.35811.6621.0017.9915730HOHs312.612-15.819-O.8361.0021.7715740,s414.9730.4832.5301.0019.4915750HOHs5_4.,-4.208-O.0841,0033.2015760HOHs619.-23.3964.5871.0025.9415770HOHs4.032-35.57411.3371.0034.7815780HOHs83.031-13.5613.0141.0045.7415790HOHs9-7.636-27.823-8.3631.0032.4415800HOHs1014.377-5.8387.3331.0031.4915810HOHs1114.741-17.1085.3961.0025.8815820HOHs1216.145-15.0866.6361.0019.5715830HOHs1314.454-14.5798.7131.0025.3715840HOHs1417.9500.0000.0001.0029.2815850HOHs1524.225-17.59614.8991.0021.3615860HOHs1615.689-1.2185.2M1.0029.8015870HOHs1712.742-15.36710.7191.0032.2315880HOHs1825.044-25.852-12.6801.0038.8115890HOHs1912.043-16.9925.7801.0036.5515900HOHs200.611-22.636-11.4101.0044.7215910HOHs218.153-26.1671.6661.0030.6615920HOHs226.953-7.1743.0821.0036.7615930HOHs2325.796-12.768-4.0271.0032.3515940HOHs24_6.819-10.006-3.3581.0047.2715950HOHs2514.330-5.78110.OS71.0028.8415960HOHs2624.391-9.50011.1171.0030.0415970HOHs2731.967-8.168-2.6811.0043.6215980HOHs2811.556-19.7025.7541.0041.4515990HOHs2915.615_8.219—13.3181.0043.5416000HOHs30-16.413-8.4365.3101.0039.8516010HOHs3113.602-9.597一14.5071.0047.9416020HOHs3218.177-27.698-1.0491.0031.5416030HOHs337.604-O.15213.2111.0049.1016040訓s3413.351-12.23316.4711.0047.3616050HOHs3528.685-IO.1084.2581.0042.0516060HOHs3614.484-2.189-0.5131.0032.3616070HOHs3713.141-15.318-15.8381.0047.6816080HOHs3825.583_6.5591.5161.0035.9316090HOHs3927.362-8.4071.0581.0041.4316100HOHs4026.116—9.09812.8981.0036.0916110HOHs4122.970-20.946—14.7851.0028.8516120HOHs4220.4952.667一4.9101.0035.8716130HOHs435.0953.273-3.2351.0047.2016140HOHs440.773-15.3775.1611.0041.2716150HOHs4516.400—1,674-8.0831.0037.60NCCcc00c0NiNiMgMgMgMg000000000000000000000000000000000000000000000表4为人源5，10-次甲基四氢叶酸合成酶与ADP的复合物的晶体坐标。表4<table>tableseeoriginaldocumentpage67</column></row><table>ATOM1NALAA-l-17.0376341_344010067.21NATOM2CAALAA_1-17.5897.665-3.69410056.32CATOM3CBALAA_1-17.4398.548-2.460100肌37CATOM4CALAA一l-16.9178.309—490410055.26cATOM50AU\A-1-16.1499.260—4.76710054.510ATOM6NALAA0-17.2197.782-6.08710046.84NATOM7CAALAA0-16.5708.212-7.32310050.89cATOM8CBALAA0-17.0687.382-8.498.0052.82cATOM9CALAA0—16.7329.703_7.6181.0054.32cATOM100ALAA0-15.76210.382-7.9531.0051.610ATOM11NMETA1-17.95610.208-7.5001.0035.55NATOM12CAMETA1-18.23611.606_7.8171.0035.65cATOM13CBMETA1-19.74011.838_7.9691.0031.45cATOM14CGMETA1-20.40510.915-8.9771.0039.79cATOM15SDMETA1-19.56010.886-10.5721.0049.17sATOM16CEMETA1-19.98012.506-11.2101.0030.92cATOM17CMETA1-17.64712.550-6.7721.0038.66cATOM180META1-17.14213.622-7.1071.0035.660ATOM19NALAA2-17.71312.149—5.5071.0040.37NATOM20CAALAA2-17.10812.930-4.4361.0045.63cATOM21CBALAA2-17.49512.362-3.0791.0039.83cATOM22CALAA2-15.59312.940-4.6011.0040.98cATOM230ALAA2-14.93313.941-4.3201.0040.050ATOM24NALAA3-15.05211.817-5.0641.0038.82NATOM25CAALAA3-13.62111.701-5.3141.0043.68cATOM26CBALAA3-13.25910.264-5.6781.0034.60cATOM27CALAA3-13.20312.654-6.4251.0032.72cATOM280ALAA3-12.20013.356一6.3111.0036.090ATOM29NALAA4-13.98912.679-7.4971.0035.81NATOM30CAALAA4-13.70113.532_8.6441.0026.73cATOM31CBALAA4一14.62113.187_9.8021.0027.09cATOM32CALAA4-13.82215.011-8.2871.0028.76cATOM330ALAA4-13.05015,839_8.7691.0030.280ATOM34NALAA5—14.79715.334—7.4441.0027.61NATOM35CAALAA5-15.00516.708一7.0021.0032.20cATOM36CBALAA5-16.25916.808-6.1451.0028.22cATOM37CALAA5-13.79017.223-6.2381.0033.93cATOM380AUA5-13.45118.405-6.31410028.580ATOM39NVALA6-13.13716.330一5.50310033.08NATOM40CAVALA6-ll.93416.685_4.76410033.44cATOM41CBVALA6-11.53015.576-3.76910033.38cATOM42CGIVALA6-10.18515.894_3.13610035.97cATOM43CG2VALA6-12.59915.404-2.70210029.20cATOM44CVALA6-IO.78316.933_5.73010030.85cATOM450VALA6-10.05917.920—5.61010026.620ATOM46NSERA7—10.62616.032—6.69410031.55NATOM47CASERA—9.57716.161-7.69810031.70cATOM48CBSERA7-9.62514.980一8,66510035.87cATOM49OGSERA了—9.58913.750-7.96110040.860ATOM50CSERA-9.72317.467一8.46810027.45cATOM510SERA-8.73518.129-8.78010038.290ATOM52NSERA8-10,96317.831一8.77510031.44NATOM53CASERA8-11.24319.072_9.48710031.86cATOM54CBSERA8-12.73719.182—9.79610027.08cATOM55OGSERA8-13.02520.368-10.51610029.580ATOM56CSERA8-10.78720.290_868810030.02cATOM570SERA8-10.16021.201-9.23310031.630ATOM58NALAA9-11.10820.304_7.39710033.05NATOM59CAALAA9—10.72621.408一6.52310028.48cATOM60CBALAA9-11.37221.248_5.1481003484ATOM61CALAA99.20821.501-6.3941.0026.20ATOM620ALAA9-8.64022.593-6.4191.0029.65ATOM63NLYSA10—8.55620.350-6.2611.0025.05ATOM64CALYSA10-7.10020.306-6.2061.0028.57ATOM65CBLYSA10—6.603.18.872—6.0101.0031.94ATOM66CGLYSA10—6.84418.295-4.62010028.80ATOM67CDLYSA丄O-6.31716.867-4.5321.0028.88ATOM68CELYSA10-6.38716.320-3.1161.0030.92ATOM69NZLYSA10_5.87914.920-3.0461.0031.41ATOM70CLYSA10-6.51220.884-7.4881.0031.65ATOM710LYSA10—5.60821.717-7.4491.0028.85ATOM72NARGA11-7.04020.432-8.62110029.76ATOM73CAARGA11-6.58720.891-9.9261.0027.65ATOM74CBARGA11-7.34420.156—11.0331.0029.19ATOM75CGARGA11-7.14920.749-12.4171.00牧58ATOM76CDARGA11-7.95419.979-13.4551.0057.40ATOM77NEARGA11一9.37419.940—13.1071.0040.25ATOM78CZARGA11-10.24020.908-13.3941.0053.81ATOM79NH1ARGA11-9.83521.992-14.0411.0052.92ATOM80NH2ARGA11-11.51220.79613.0371.0049.16ATOM81CARGA11—6.76222.398—10.0771.0029.84ATOM820ARGA11—5.85023.095-10.5221.0030.08ATOM83NSERA12一7.93722.柳-9.7061.0033.81ATOM84CASERA12-8.21324.326-9.7961.0033.67ATOM85CBSERA12—9.66724.629_9.4231.0033.93ATOM86OGSEKA12-10.53424.397—10.5201.0041.64ATOM87CSERA12-7.25725.138_8.9261.0032.05ATOM880SERA12—6.78726.200-9.3321.0032.31ATOM89NLEUA13—6.96524.630-7.7331.0028.35ATOM90CALEUA13_6.07625.324-6.8081.0031.76ATOM91CBLEUA13-6.14224.690-5.4171.0028.56ATOM92CGLEUA13一5.45725.466-4.2891.0029.23ATOM93CD1LEUA13-5.85226.939-4.3131.0025.00ATOM94CD2LEUA13-5.77824.843-2.9411.0024.99ATOM95CLEUA13—4.63925.340-7.3181.0024.38ATOM960LEUA13-3.93026.332-7,1601.0028.27ATOM97NARGA14-4.21224.238-7.9281.0025.28ATOM98CAARGA14-2,86824.151-8.4881.0029.22ATOM99CBARGA14—2.60722.756-9.0631.0026.33ATOM100CGARGA14—2.54621.653_8.0151.0037.22ATOM101CDARGA14一l.98020.368_8,5991.0032.80ATOM102NEARGA14_2.03819.264-7.6441.0033.51ATOM103CZARGA14-2.94818.296_7.6721.0040.03ATOM104NH1ARGA14_3,88218.282_8.6141.0036.84ATOM105NH2ARGA14_2.92117.336_6.7591.0035.60ATOM106CARGA14_2.64425.218-9.56010031.22ATOM1070ARGA14-1.62325.904-9.56210028.32ATOM108NGLYA15-3.60825.354-10.46510034.73ATOM109CAGLYA15-3.53526.358-11.51010032.22ATOM110CGLYA15-3.47627.756-10.92910033.44ATOM1110GLYA15-2.68328.592-11.36310037.08ATOM112NGLUA16一4.32328.008_9.93710030.90ATOM113CAGLUA16—4.34029.292_9.24710040.01ATOM114CBGLUA16一5.49729.338-8.25010031.39ATOM115CGGUJA16—5.37330,419—7.19210044.27ATOM116CDGLUA16_6.53130.403一6.21310076.03ATOM1170E1GLUA16-7.57929.808—6.54410065.38ATOM1180E2GLUA16-6.39630.983_5.11510066.94ATOM119CGLUA16_3.02029.548_8.5291004349ATOM1200GLUA16-2.49930.664一8.54510037.47ATOM121NLEUA17-2.48228.505—7.90510037.86ATOM122CALEUA17-l.22828.611-7.1661003269ATOM123CBLEUA17一l.01627.3746.2881003101ATOM124CGLEUA17_1.90427.272—5.0461003679ATOM125CD1LEUA17_1.77025.902-4.4001003400ATOM126CD2LEUA17_1.57128.378-4.0541003336ATOM127CLEUA17—0.04128.800—8.1001003734CCONCCCCCNCONCCCCNCNNCONCCOCONCCCCCCONCCCCNCNNCONCCONCCCCOOCONCCCCCCATOM128ATOM129ATOM130ATOM131ATOM132ATOM133ATOM134ATOM135ATOM136ATOM137ATOM138ATOM139ATOM140ATOM141ATOM142ATOM143ATOM144ATOM45ATOM146ATOM147ATOM148A丁OM]49ATOM150ATOM151ATOM152ATOM153ATOM154ATOM155ATOM156ATOM157ATOM158ATOM159八TOM160「m5lATOM161LU"D」ATOM162ATOM163ATOM164ATOM165ATOM166ATOM167ATOM168ATOM169ATOM170ATOM171ATOM172ATOM173ATOM174ATOM175ATOM176ATOM177ATOM178ATOM179ATOM180ATOM181ATOM182ATOM183ATOM184ATOM185ATOM186ATOM187ATOM188ATOM189ATOM190ATOM191ATOM192ATOM193ATOM194ATOM195A170.85129.601-7.8241.0036.66A18—0.02828.065■-9.2081.0036.00A181.06728.174-10.1661.0037.03A180.99327.071-11.2231.0029.44A181.10425.670-10.6571.0043.79A181.93024.767-11.5571.0064.46A183.41725.048-11.3931.0072.85A184.25624.044-12.1051.0054.36A181.09429.544-10.8331.0038.69A182.16230.069—11.1431.0048.34A19—0.08330.118-11.0581.0037.19A19_0.16731.459-11.6191.0036.50A19-1.61831.864-11.8261.0038.43A190.54432.452-10.7051.0050.52A191.37233.244—11.1561.0046.79A200.22132.398-9.4161.0039.87A200.85233.273-8.4311.0042.52A200.27033.031-7.0331.0039.21A2011833.618-6.8281.0045.85A20一l.39633.920-5.3591.0063.77A20-2.07932.826-4.6761,0070.37A20_2.43332.858-3.3951.0070.83A20-2.16133.927-2.6601.0069.57A20-3.05531.822-2.8471.0052.65A202.36733.089-8.4031.0037.06A203.11834.062-8.3591.0044.20A212.80831.836-8.4271.0041.16A214.22931.522-8.3591.0040.58A214.43430.014-8.2151.0034.91A213.95529.411-6.8951.0039.30A213.74827.907-7.0181.0041.64A214.93529.737-5.7781.0043.03A214.98932.047-9.5731.0046.65A216.06132.639_9.4361.0045.55A224.43231.826一IO.7591.0046.33A225.05832.284-ll.9931.0044.66A224.27731.779-13.2001.0040.64A225.16233.805-12.0261.0044.52A226.03734.361-12.6891.0053.10A234.27634.471--11.2921.0050.29A234.21735.929-ll.2931.0039.99A232.79736.402-ll.0131.0039.59A235.19536.561-10.3051.0058.87A235.32337.783-10.2481.0044.40A245.87935.730-9.5271.0062.12A246.86936.227_8.5801.0052.90A247.11035.212_7.4601.0045.20A245.92334.998-6.5351.0043.03A246.31633.864-5.1931.0054.04A247.72334.697_4.4601.0041.08A248.18436.538_9.2821.0041.91A248.60135.820-10.1901.0052.38A258.83337.617-8.8591.0046.46A2510.13637.978-9.4001.0043.54A2510.48639.426_9.0451.0049.34A2510.57739.596—7.6391.0044.45A.2511.20637.030-8.腳1.0043.82A2511.04336.429-7.8081.0046.67A2612.29836,895—9.6131.0043.13A2613.37835.999一9.2221.,00肌66A2614.41035.895-10.3321.0039.22A2614.03536.453-7.9221.0046.94A2614.44535.630-7.1031.,0040.18A2714.13137.765-7.7391,■0041.77A2714.78438.328—6.5631.0045.37A2715.21139.774一6.8261..0049.26A2714.08840.683-7.2941,,0056.79A2714.58742.058一7.6851.,0058.430NCccccNc0Nccc0NccccNcNNC0NCccccc0Nccc0Nccc0Ncccscc05910.91229.364-9.0201.0044.32609.90827.355一9.0241.0040.92608.72527.835—8.3141.0035.98607.44527.401—9.0341.0039.33607.35725.899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.5241.0058.270HETATM16940HOHS6812.64816.93219.9531.0063.670HETATM16950HOHS694.88038.339-5.1701.0060.940HETATM16960匪S7030.02112.8553.7351.0048.020HETATM16970HOHS7114.11139.633-11.1561.0064.770HETATM16980HOHS7227.0218.157-1.0671.0042.970HETATM16990■s7318.9358.79020.8631.0054.900HETATM17000HOHs7424.1856.910-1.2991.0045.770HETATM17010HOHs7515.3871.164-5.0261.0042.030HETATM17020HOHs768.47718.645-5.9371.0043.470HETATM17030HOHs778.3632.578-10.5591.0056.030HET扁17040腦s783.18136.918-6.8501.0056.060HETATM17050HOHs79-2.02116.9243.0491.0040.750HETATM17060HOHs8020.54122.038-7.6991.0050.640HETATM17070,s818.204-O.9372.4591.0042.920HETATM17080HOHs823.84021.262—11.7691.0051.240HETATM17090HOHs8313.24638.061-13.2291.0053.930HETATM17100■s8424.3935.304-13.5561.0056.210HETATM17110HOHs85—1.75428.341-14.3321.0047.120HETATM17120HOHs861.70214.012-2.5071.0040.630HETATM17130■s87-2.97516.490-3.0061.0040.640HETATM17140HOHs8816.8031.805-7.9881.0054.360HETATM17150HOHs8917.46721.749—20.1161.0054.420HETATM17160HOHs90-5.94027.5036.7331.0044.080HETATM17170■s917.23623.881-1.5141.0045.130HETATM17180■s92—0.13919.52511,7271.0049.040HETATM17190HOHs93_8.17929.545-2.3651.0064.320HETATM17200HOHs9415.69424.678-12.8991.0058.060HETATM17210HOHs9513.6479.99214.8691.0060.680HETATM17220腦s96-l.64710.621-2.4871.0052.230HETATM17230HOHs9715.7561.9917.9821.0052.310HETATM17240■s9823.32020.324-16.1091.0060.970HETATM17250HOHs993.753-2.5432.9921.0059.020IIETATM17260HOHs10025.9413.0543.5671.0049.410HETATM17270HOHs101-3.00310.116-6.8541.0053.540HETATM17280HOHs1026.379-3.0343.5101.0046.170HETATM17290HOHs1035.39713.78710.3261.0053.370HETATM17300HOHs104_8.67424.9546.1681.0049.770HETATM17310HOHs10518.4059.959-12.9881.0062.470HETATM17320HOHs10619.61522.180-16.5601.0050.980HETATM17330■s10712.77815.604-10.5901.0038.560HETATM17340HOHs1082.05314,7862.0511.0039.550HETATM17350s109—8.49516.67911.1071.0061.640HETATM17360HOHs110-4.64411.809-2.1971.0052.300HETATM17370鹏s11118.0603.814-9.2721.0048.120HETATM17380HOHs11224.25615.79514.9141.0048.680HETATM17390■s11322.07715.85316.8521.0058.750HETATM17400HOHs114-11.62327.3647.3501.0058.930HETATM17410HOHs11525.68929.034-6.2131.0062.100HETATM17420,s116-15.36620.610-7.2141.0057.380HETATM17430HOHs11727.44626.3829.7841.0052.130HETATM17440■s118一O.7806.946_1.2151.0067.580HETATM17450■s11932.40714.4163.9411.0061.020HETATM17460HOHs120_3.18014.315-IO.1761.0049.300HETATM17470HOHs121-13.63623.435—6.9821.0055.460HETATM17480HOHs12216.12326.725-9.2261.0062,320HETATM17490HOHs123—5.79113.788_7.7941.0054.450HETATM17500■s12416.36215.222_6.5161.0024.410HETATM17510■s12512.44615.9371.0561.,0025.060HETATM17520腳s12614.56517.219一5.2971..0024.180HETATM17530HOHs12716.9365.592-11.1621.0043.070HETATM17540HOHs12814.6765.669—9.8911.0051.760HETATM17550HOHs130-9.54212.446-10.6041.0064.680HETATM17560HOHs13112.96924.225-12.3561..0045.160HETATM17570HOHs13319.39729.024—0.5951.,0060.320HETATM17580■s13432.30111.柳2.6161,■0068.250HETATM17590HOHs1351.87715.851一12.7541..0056.83093表5为人源5，10-次甲基四氢叶酸合成酶与N5_亚胺磷酸过渡态的复合物的晶体的坐标。表5-8.49020.4807.2511.0048.11-2.08213.1198.0061.0052.530.00334.7674.9691.0044.34-12.84223.141一9.7161.0056.1610.21725.03516.8241.0059.342.8862.2254.5301.0062.0122.88828.011—7.3551.0064.535.94824.677-5.9451.0046.648.07830.204-10.6231.0071.164.00614.855-11.6731.0030.008.54115.171-9,9461.0030.001.43714.27011.3711.0030.00-4.14921.62113.5861.0030.00-9.97227.847-6.2001.0030.005.35932.01310.3721.0030.0031.2256.3801.4421.0030.000.83822.59612.1511.0030.00HETATM17600HETATM17610HETATM17620HETATM17630HETATM17640HETATM17650HETATM17660HETATM17670HETATM17680TER1769ATOM17700ATOM17710ATOM17720ATOM17730ATOM17740ATOM1775MGATOM1776NiATOM1777MGEND-9<u1_-344789<u1114445HHHHHHHHHHHHHHHiOOOOOOOOOOOOOOOGNGHHHHHHHHHHHHHHHMM941NMETA工16.3439.3557.94510034.02NATOM2CAMETA117.27710.5138.14310034.81CATOM3CBMETA11873310.0558.13710034.30CATOM4CGMETA119.3619.9369.53310034.35cATOM5SDMETA119.65111.53210.34610037.39sATOM6CEMETA120.36412.5219.02510032.27cATOM了CMETA117.08211.6297.12410035.19cATOM80META116.90012.7997.49410035.270ATOM9NALAA217.13411.2685.84510034.49NATOM10CAALAA216.72212.1714.77910034.40cATOM11CBALAA217.02811.5653.4291.0034.16cATOM12CALAA215.22612.4084.9211.0035.41cATOM130ALAA214.73213.5044.6341.0035.550ATOM14NALAA314.52311.3645.3761.0035.44NATOM15CAALAA313.08411.4055.6281.0035.26cATOM16CBALAA312.56110.0005.9641.0034.46cATOM17CALAA312.77912,3906.7591.0035.66cATOM180ALAA311.78113.1186.7201.0036.160ATOM19NALAA413.65912.4217.7551.0035.37NATOM20CAALAA413.51713.3328.8751.0035.04cATOM21CBALAA414.45412.93310.Oil1.0034.53cATOM22CALAA413.66614.8188.4871.0035.13cATOM230ALAA412.82915.6238.8741.0035.350ATOM24NALAA514.68615.1857.7061.0035.28NATOM25CAALAA514.85916.6017.2741.0035.00cATOM26CBALAA516.17416.7946.5561.0033.55cATOM27CALAA513.70817.1016.4011.0035.80cATOM280ALAA513.35118.2816.4471,0035.620ATOM29NVALA613.15716.1865.5971.0035.95NATOM30CAVALA611.90316.3904.8521.0036.31cATOM31CBVALA611,56715.1473.9391.0036.61cATOM32CGIVALA610.24515.3323.2251.0036.90cATOM33CG2VALA612.67514.8792.9121.0036.14cATOM34CVALA610.71416.7175.7991.0036.34cATOM350VALA69.90217.6025.5011.0036.520ATOM36NSERA710.62516.0146,9351.0036.23NATOM37CASERA了9.54316.2337.9161.0036.04cATOM38CBSERA79.36515.0188.83110035.80cATOM39OGSERA79.02213.8698.0761.0035.560ATOM40CSERA79.75717.4948.7431.0035.72cATOM410SERA78.79418.1529.1471.0035.800ATOM42NSERA811.02217.8169.0011.0035.39NATOM43CASERA811.38119.1039.5701.0035.29cATOM44CBSERA812.90419.2459.6451.0035.24cATOM45OGSERA813.28220.34110.46010034.910ATOM46CSERA810.76720.1828.6811.0035.40cATOM470SERA89.95620.9819.1441.0035.460ATOM48NALAA911.12420.1387.3931.0035.75NATOM49CAALAA910.65921.0736.3561.0035.63cATOM50CBALAA911.17720.6504.99910035.19cATOM51CALAA99.15121.2076.31310035.74cATOM520ALAA98.62222，3236.23610035.860ATOM53NLYSA108.46420.0666.3591.0035.72NATOM54CALYSA107.00720.0426.37310035.34cATOM55CBLYSA106.47518.6076.18910035.89cATOM56CGLYSA106.743.17.9754.80310035.39cATOM57CDLYSA105.95916.6874.61210035.34cATOM58CELYSA106.74115.6813.78210036.74cATOM59NZLYSA105.95115.1242.61610038.06NATOM60ATOM61ATOM62ATOM63ATOM64ATOM65ATOM66ATOM67ATOM68ATOM69ATOM70ATOM71ATOM72ATOM73ATOM74ATOM75ATOM76ATOM77ATOM78ATOM79ATOM80ATOM81ATOM82ATOM83ATOM84ATOM85ATOM86ATOM87ATOM88ATOM89ATOM90ATOM91ATOM92「ni^lATOM93LUIOJ」ATOM94ATOM95ATOM96ATOM97ATOM98ATOM99ATOM100ATOM101ATOM102ATOM103ATOM104ATOM105ATOM106ATOM107ATOM108ATOM109ATOM110ATOM111ATOM112ATOM113ATOM114ATOM115ATOM116ATOM117ATOM118ATOM119ATOM120ATOM121ATOM122ATOM123ATOM124ATOM125ATOM126ATOM12735.06C35.05035.28N35.05C35.16C35,03C35.48C35.57N35.25C34.56N34.61N34.75C34.50034.69N35.12C35.50C35.99035.22C35.48035.06N34.71C34.75C34.22C33.98C34.48C34.80C34.83034.93N34.67C34.56C34,50C35.05C34.75N34.67C34.62N34.67N34.94C34，93035.07N35.17C35.50C35.64035.47N35,85C35.98C36.51C37.57C36,95038.34035.72C36.08035.69N34.96C34,57C34.35C33.87C34.13C35.08C35.49035,29N35,20C34.52C34.62C34.79C35.36C36.16N35.37C35.620106，46720.6927.659105,59221.5647.600117.01320.2918.808116,57720.80010,110117.36020.08911,220116-84420.27312.647117.98820.01013.620119.26820.38813.0001110.05421.39313,388119,73322.13714,44911.18021.63212.715116.70022.33610.197115.70523.03010.434127.91222.8529.985128.15924.2999.884129.49924.5889.1891210.58123.8949.794127.06224.9879.089126.28125.7709,635137,01224.6647.797136.07425.2576.843136.30524.6645.441135.71925.2904，165136.14026.7273.930136.14324,4522.996134.60425.1687.281133.82226.0596-969144,23724.1188.020142.90924.0468.652142.68322.6969,317142，謹21.5478,387141-81420.4578.716141,83219.4087.695142.53218.2807.785143.26918.0288.867142，48417,4006.794142.72125.1359,701141.65325.7249.800153.75425.38310.502153.67126.38111.553153.49427.72210,889152,48128,40711,080164.46928.08410'069164，40729.3619.378165,52329.4848.344165.62530.8757.731166.07630,8396.274166.90029,9565,896165.59931,7065.505163.04729.5628.717162.45730,6278.853172,56428.5268,021171.28128.5707.310171.08027.3636,386171.69927.3564.976171.66725.9494.389171.01528.3314,031170.10928.6978.25317一O.82329.4377.956180.14927.9949,38718_0,91428.12010,38818_0.84427.01011.42318—0.86725.62410，82118—1.21324.54111,S3618_2.71824.30111.86218—3.07922,84411.92518-o.87629.49911,05518一l.91929.99411.504SSGGGGGGGGGGGRRRRRRUUUUUUUUGGGGGGGGGGGYYYYUUUUUUUUUUUUUUUUUSSSSSSSSS1212121212ABGDEZHHABGABGDDABGDEZHHA:ACDGDEEABGDDABGDENICONCCCCNCNNCONCCOCONCCCCCCONCCCCNCNNCONCCONCCCCOOCCDNCCCCCCONCCCCCNCOoooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooo<table>tableseeoriginaldocumentpage97</column></row><table>ATOM196CZARGA29-13.94729.3316.5771.0031.72CATOM197NH1ARGA29-15.00229.9227.1251.0031.81NATOM198NH2ARGA29-13.79528.0176.6911.0031.46NATOM199CARGA29-12.99234.1663.8451.0033.79CATOM2000ARGA29-12.93633.3592.8901.0033.520ATOM201NLEUA30-14.10034.8614.1461.0033.80NATOM202CALEUA30-15.33434.7533.3431.0033.45CATOM203CBLEUA30-16.52835.4144.0331.0033.67CATOM204CGLEUA30-16.99534.7855.3491.0034.30cATOM205CD1固A30-17.73235.8106.2181.0034.57cATOM206CD2LEUA30-17.84833.5315.1381.0033.97cATOM207CLEUA30-15.17535.3281.9431.0033.20cATOM2080LEUA30-15.65334.7270.9781.0033.370ATOM209NARGA31-14.50436.4781.8371.0033.10NATOM210CAARGA31-14.30437.1610.5521.0032.72cATOM211CBARGA3113.49038.4550.7361.0032.81cATOM212CGARGA31-13.07539.106_0.5821.0032.51cATOM213CDARGA31-12.08840.231_0.4041.0032.09cATOM214NEARGA31-IO.70639.773-O.2301.0031.96NATOM215CZARGA31-9.89639.375—1.2111.0031.81cATOM216NH1ARGA31-10.32139.340-2.4731.0030.32NATOM217NH2ARGA31-8.65338.985-0.9111.0031.88NATOM218CARGA31-13.63036.243-0.4831.0032.20CATOM2190ARGA31—14.15736.012-l.5801.0032.240ATOM220NGLNA32-12.46835.719_0.1021.0031.98NATOM221CAGLNA32-ll.63734.893-o.9641.0031.72CATOM222CBGLNA32-10.33334.572-o.2331.0031.66cATOM223CGGLNA32-9.05735.028-o.9251.0031.17cATOM224CDGLNA32-7.85334.958-l.0001.0031.20cATOM2250E1GLNA32—7.80235.6431.0171.0031.960ATOM226NE2GLNA32一6.87734.137-o.3531.0030.78NATOM227CGLNA32-12.38833.611-l.3381.0031.61cATOM2280GLNA32-12.18533.072-2.4251.0031.040ATOM229NSERA33-13.25833.150-O.4321.0031.90NATOM230CASERA33-14,14132.004-O.6601.0031.20cATOM231CBSERA33-14.78631.5450.6451.0031.24cATOM232OGSERA33-13.81231.0931.5641.0031.100ATOM233CSERA33-15.21732.325_1.6871.0031.35cATOM2340SERA33-15.45131.541-2.6061.0031.350ATOM235NARGA34-15.86933.477-1.5511.0031.68NATOM236CAARGA34-16.77433.965-2.6151.0031.88cATOM237CBARGA34-17.30435.361-2.2871.0033.05cATOM238CGARGA34-18.80735.447-2.0741.0034.15cATOM239CDARGA34-19.19336.861-l.6211.0035.19cATOM240NEARGA34-19.13936.989-0.1561.0034.99NATOM241CZARGA34-19.11538.1410.5141.0035.64cATOM242NH1ARGA34-19.12439.314_0.1361.0036.01NATOM243NH2ARGA34-19.06638.1171.847〗.DO35.58NATOM244CARGA34-16.12933.990-4.0141.0031.50CATOM2450ARGA34-16.81833.780_5.0141.0031.730ATOM246NVALA35-14.81634.230_4.0831.0031.20NATOM247CAVALA35-14.11634.312_5.3761.0030.76CATOM248CBVALA35-12.88135.246_5.3141.0030.82cATOM249CGIVALA35-12.25635.404—6.6761.0030.70cATOM250CG2VALA35-13.29636.608-4.8171.0031.39cATOM251CVALA35-13.78932.936—5.9941.0030.92cATOM2520VALA35-14.09732.690-7.1721.0031.250ATOM253NLEUA36-13.19532.038_5.2011.0030.91NATOM254CALEUA36-12.95030.651-5.6321.0030.38cATOM255CBLEUA36-12.19029.870一4.5631.0029.61cATOM256CGLEUA36-10.66529.920—4.6041.,0029.83cATOM257CD1LEUA36-10.15231.188_3.9851,,0030.58cATOM258CD2固A36-10.12428.764_3.8381.,0029.69cATOM259CLEUA36-14.23729.918-5.9841.,0030.04cATOM2600LEUA36-14.28329.173—6.9591.,0030.200ATOM261NSERA37-15.27830.132_5.1881.0029.70INATOM262CASERA37-16.58629.573一5.4851..0030.05cATOM263CBSERA37—17.64130.243—4.6271,,0030.58c<table>tableseeoriginaldocumentpage99</column></row><table>ATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOM-16.65922.497-11.3531.0027.5917.90922.461-10.5041.0027.27-18.02021.579-9.4261.0026.98-19.17021.529-8.6501.0026.70-20.23322.341-8.9741.0027.25-21.38922.277-8.2331.0027.56-20.15523.215-10.0441.0027.41-18.99723.270-10.8011.0027.46-17.76621.030-13.1001.0027.98-18.60020.159-12.8351.0028.26-17.87721.807-14.1701.0028.09-19.06921.731-15.0121.0028.04-18.98522.749—16.1481.0027.93-19.43524.116-15.7151.0028.12-19.00425.207-16.6751.0029.62-18.47324.946-17.7781.0029.29-19.22526.461-16.2611.0029.92-19.34520.319-15.5331.0027.79-20.44019.799-15.3511.0027.66-18.33319.704-16.1441.0028.11-18.42418.357-16.7381.0027.88-17.16818.063-17.5801.0027.86-16.98019.055-18.7561.0028.32-15.67718.814-19.5291.0028.63-15.16520.102-20.2091.0029.11-15.33320.238-21.7051.0028.63-18.69017.207-15.7571.0027.78—19.24716.192-16.140.0027.80-18.32817.372-14.4891.0028.24-18.30416.240-13.5531.0027.62-17.17216.395-12.5311.0027.65-17.63317.077一ll.3721.0028.14-19.64015.932-12.8621.0027.41-20.47816.807-12.6661.0027.27-19.80114.668-12.4771.0027.67-21.06914.142-12.0021.0027.32-21.54113.041-12.9531.0027.62-21.68813.570-14.3931.0028.12-21.53812.509—15.4951.0028.41-21.71913.158-16.8821.0028.76-20.510IS-929-17.3071.0028.24-20.942IS.642一IO.5731.0027.51-21.69914,074-9.6841.0027.91-19.98512.744一IO.3281.0027.35-19.77212.245-8.9601.0027.07-19.58610.726_8.9401.0026.87-20.5919.980-9.8391.0026.65-20.2018.523-10.1161.0026.31-19.7797.843_8.9021.0026.34-20.6077.346-7.9911.0026.62-21.9257.414-8.1551.0026.60-20.1116.766-6.9101.0027.16-18.58212.994-8.3901.0026.57-17.48212.899-8.9181.0026.34-18.85413.765-7.3351.0026.65-17.94414.741_6.7581.0026.08-18.54216.178_6.8461.0026.42-18.37816.708-8.2891.0026.82-18.39118.182-8.4581.0026.59-17.92017.128_5.8011.0026.09-17.66414.428—5.3151.,0026.16-18.57614.121_4.5641.,0026.50-16.39714.504—4.9321..0026.20-16.02214.511-3.5261.0026.25-14.90013.511_3.2561..0026.27-14.31213.767_1.9861.,0025.88-15.58015.915-3.0961,,0026.06—14.76516.546—3.7741,■0026.18100332CBTYRA333CGTYRA334CD1TYRA335CE1TYRA336CZTYRA337OHTYRA338CE2TYRA339CD2TYRA340CTYRA3410TYRA342NGLNA343CAGLNA344CBGLNA345CGGLNA346CDGLNA3470E1GLNA348NE2GLNA349CGLNA3500GLNA360361362363364365366367368369370371372373374375376377378379380381382383384385386387388389390391392393394395396397398399NCACBOGC0NCACBCGCDCENZC0NCACBCGCDNECZSERSERSERSERSERSERLYSLYSLYSLYSLYSLYSLYSLYSLYSARGARGARGARGARGARGARG隨ARGNH2ARGCARG0ARGNILECAILECBILECGIILECD1IL￡CG2ILECILE0NCACBOGC0ILESERSERSERSERSERSER4646464646464646464647474747474747474748484848484848484849494949494950505050505050505051515151515151515151515252525252525252535353535353CCCCCOCCCONCCCCONCONCCCCCNCONCCOCONCCCCCNCONCCCCNCNNCONCCCCCCONCCOCOsssssssssYYYYYYYYY-9-5ATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOMATOM54-16.l(M16.374-1.9571.0025.9854-15.85117.711-l.4361.0025.9254-16.90918.731-1.9381.0025.8354-16.36520.167-l.8261.0025.9554-17.33621.243-2.1641.0026,2854-18.27018.513-1.2591.0025.4754-15.82017.6740.0881.0026.4254-16.47516.8310.7051.0026.6255-15.05118.5800.6961.0026.7455-14.81918.5672.1401.0026.7055-13.32818.7932.4751.0026.7855-12.76020.0741.9211.0027.1655-12.76321.2412.6731.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.0131.0048.49-6.79013.42413.5791.0048.49_7.25813.88112.2441.0048.49-6.39914.45311.2911.0048.49-4.98214.56411.6521.0048.49-4.53614.18912.9871.0048.49-5.07113.12915.4021.0048.49-5.85412.95516.2731.0048.49-3.65212.83615.5891.0048.49-3.00812.28616.7831.0048.49-2.35010.97416.3371.0048.49-1.50811.08615.0661.0048.49_0.35110.12914.9261.0048.49_0.6239.00214.9611.0048.490.97310.51415.1271.0048.49_2.04113.19217.5811.0048.49-l.99914.36417.4331.0048.49-l.13012.61318.4641.0048.49-6.80214.5905.4761.00肌02-5.61514.6805.3611.0047.65-10.70213.05014.5301.0031.15-14.6735.5977.3361.0027.97-20.7406.2048.0771.0029.10-23.9576.229-6.7641.0027.52-7.67332.366-2.3911.0031.16—18.89223.5384.6271.0026.66-24.3639.50710.9321.0030.36-25.56513.173-3.5631.0027.159.43627.9115.5221.0032.70—12.41615.831_1.0381.0026.55一4.073_3.421—4.0781.0030.20-7.82726.6122.4111.0030.44-8.069-l.856-9.4281.0031.50一6.906_3.410-3.7351,0030.31-18.81829.6787.6641.0029.24—14.12915.264-15.0391.0028.09-15.28517.0645.1071.0026.99_7.1947.1133.4651.0029.7716.05714.5722.6721.0032.14-7.956-4.973-2.2111.0028.73-17.1761.9848.6821.0026.17-20.0901,6478.8661.0026.798.51828.5957.8511.0035.463.75318.1971.5661.0033.51-26.5355.383-7.1701.0030.42-3.86813.618_8.4691.0028.65-13.77710.074-14.2451.0027.50-13.51932.93611.7581.0031.667'61811.292-4.9601.0034.19—4.33114.5354.8331.0030.00一4.23615.7173.9731.0030.00-5.74714.4385.3101.0030.00.84813.4503.9401.0030.00NCNNC0cNccNccNccccccc0Ncccc00c00c000000000000000000000000000000p00-3,38914.6555.9661.0030.0000HETATM1556HETATM1557HETATM1558HETATM1559HETATM1560HETATM1561H已TATM1562HETATM1563HETATM1564阻ATM1565HETATM1566HETATM1567HETATM1568HETATM1569HETATM1570H已TATM1571HETATM1572HETATM1573HETATM1574HETATM1575HETATM1576HETATM1577HETATM1578HETATM1579HETATM1580HETATM1581HETATM1582HETATM1583HETATM1584HETATM1585HETATM1586HETATM1587HETATM1588HETATM1589TER1590ATOM1591ATOM1592ATOM1593ATOM1594ATOM1595ATOM1596ATOM1597ATOM1598ATOM1599ATOM1600ATOM1601ATOM1602ATOM1603ATOM1604ATOM1605ATOM1606ATOM1607ATOM1608ATOM1609ATOM1610ATOM1611ATOM1612ATOM1613ATOM1614ATOM1615ATOM1616ATOM1617ATOM1618ATOM1619TER1620ATOM1621ATOM1622ATOM1623ATOM162403ATOM162504ENDP04C1P04C1t5一-5I-7_i3_12A34445678891111111ACDGDEET12P-NCNNCOCNCCNCCNCCCCCCCONCCCasosooG-表6为人源5，10-次甲基四氢叶酸合成酶与10-甲酰四氢叶酸的复合物的晶体的坐标。表6<table>tableseeoriginaldocumentpage119</column></row><table>ATOM60CGLYSA10—6.97818.423—4.5021.0016.72CATOM61CDLYSA10-6.49116.卿-4.3931.0018.87CATOM62CELYSA10-6.67916.柳-2.9961.0024.73CATOM63NZLYSA10一6.06515.109_3.0281.0030.06NATOM64CLYSA10-6.61820.927-7.3891.0019.40CATOM650LYSA10-5.74521.745-7.3811.0017.750ATOM66NARGA11-7.16620.498-8.51510020.52NATOM67CAARGA11-6.67820.973-9.8001.009.97CATOM68CBARGA11-7.48320.210-10.8941.0022.78CATOM69CGARGA11-7.05220.503-12.3101.0027.16cATOM70CDARGA11-8.07719.792-13.3101.0030.78cATOM71NEARGA11-9.51719.884-12.9271.0032.13NATOM72CZARGA11-10.27020.996—13.0641.0034.21cATOM73NH1ARGA11-9.70722.107-13.5571.0039.27NATOM74NH2ARGA11-ll.54921.033-12.6881.0033.87NATOM75CARGA11-6.85322.柳_9.9331.0019.33CATOM760ARGA11-5.94623.198-10.3461.0019.800ATOM77NSERA12-8.03722.956-9.5871.0020.92NATOM78CASERA12-8.27224.柳-9.6591.0023.61CATOM79CBSERA12-9.69724.630-9.2111.0024.33cATOM80OGSERA12-9.96526.0089.1581.0038.060ATOM81CSERA12-7.30625.227—8.7841.0023.14cATOM820SERA12-6.72626.218-9.2251.0022.990ATOM83NLEUA13一7.09124.761-7.5601.0021.66NATOM84CALEUA13_6.15525.436-6.6751.0020.39cATOM85CBLEUA13-6.33224.咖-5.274].0020.35cATOM86CGLEUA13—5.42825.508-4.2081.0019.96cATOM87CD1LEUA13-5.51127.078-4.1441.0023.01cATOM88CD2LEUA13-5.84324.814-2.8431.0022.60cATOM89CLEUA13一4.69025.400-7.1791.0020.94cATOM900LEUA13一3.94526.379-7.0911.0022.530ATOM91NARGA14一4.26424.260-7.6991.0019.67NATOM92CAARGA14-2.98524.183-8.3691.0020.36cATOM93CBARGA14-2.71222.769_8.9711.0019.14cATOM94CGARGA14-2.57921.652-7.9461.0020.25cATOM95CDARGA14一l.99620.356-8.6171.0024.75cATOM96NEARGA14一2.14819,278-7.6441.0022.35NATOM97CZARGA14-3.09518.376-7.6221.0025.18cATOM98NH1ARGA14一3.97918.279-8.6591.0025.58NATOM99NH2ARGA14-3.13617.549-6.5831.0024.35NATOM100CARGA14-2.78225.230-9.4451.0021.71CATOM1010ARGA14-l.70025.875—9.5051.0020.430ATOM102NGLYA15-3.81525.400一IO.2881.0021.46'NATOM03CAGLYA15-3.74626.437-11.3411.0022.24CATOM104CGLYA15-3.61927.810-10.7301.0023.70cATOM1050GLYA15-2.76628.575-11.14210025,990ATOM106NGLUA16-4.39128.093-9.6781.0025.41NATOM107CAGLUA16-4.23729.376-9.0031.0028.27cATOM108CBGLUA16-5.28029.515-7.89310028.10cATOM109CGGLUA16-6.71129.638-8.45510038.56cATOM110CDGLUA16一7.82029.458-7.39210047.80cATOM1110E1GLUA16-7.64229.930-6.24210054.010ATOM1120E2GLUA16一8.87128.842-7.70510052.970ATOM113CGLUA16-2,81629.623_8.45910025.89cATOM1140GLUA16-2.20230.675-8.69410025.080ATOM115NLEUA17-2.30728.635一7.71310025.82NATOM116CALEUA17-O.99628.708-7.08510024.51cATOM117CBLEUA17_0.72127.449一6.24110023.46cATOM118CGLEUA17-1.61327.418-5.00310025.55cATOM119CD1LEUA17-1.67926.024一4.43410022.90cATOM120CD2LEUA17-1.07828.428_3.94210028.78cATOM121CLEUA170.05228.830一8.11210023.52cATOM1220LEUA170.92129.670_7.98010024.680ATOM123NLYSA180.01227.卿-9.16010024.83NATOM124CALYSA181.02828.084-10.20310024.07cATOM125CBLYSA180.81327.031-ll.29410025.24cATOM126CGLYSA181.36325.632—10.90310027.02cATOM127CDLYSA180.76024.510—11.76210034.65c120CN101781637A说明书117/143页ATOM128ATOM129ATOM130ATOM131ATOM132ATOM133A簡134ATOM135ATOM136ATOM137ATOM138ATOM139ATOM140ATOM141ATOM142ATOM143ATOM144ATOM145ATOM146ATOM147ATOM148ATOM149ATOM150ATOM151ATOM152ATOM153ATOM154ATOM155ATOM156ATOM157ATOM158ATOM159ATOM160「,lATOM161LUiyi」ATOM162ATOM163ATOM164ATOM165ATOM166ATOM167ATOM168ATOM169ATOM170ATOM171ATOM172ATOM173ATOM174ATOM175ATOM176ATOM177ATOM178ATOM179ATOM副ATOM181ATOM182ATOM183ATOM184ATOM185ATOM186ATOM187ATOM188ATOM189ATOM190ATOM191ATOM192ATOM193ATOM194ATOM195181.70723.320-11.9301.0035.17183.15123.735-11.9901.0035.12181.訓29.448-10.8601.0025.08182.19429.896-11.2241.0026.0819-O.04430.091-ll.0521.0025.9819-O.06431.396-11.6771.0028.0419-l.47031.827-11.8841.0028.55190.65632.422-10.7811.0030.11191.54533.211-11.2691.0029.80200.31432.425-9.4901.0029.52201.09533.256-8.4961.0031.56200.53233.104-7.1011.0031.9520-0.90933.176-7.0881.0036.3420-l.43432.587—5.8391.0045.3320-l.30733.535一4.7671.0051.7820_1,88133.391-3.5771.0056.5920-2.64732.307-3.2971.0054.1920-1.69534.359—2.6661.0058.80202.57632.969—8.4421.0030.84203.42233.874—8.3771.0032.15212.92031.688-8.4741.0032.21214.32531.352一8.4801.0031.38214.52129.881-8.2261.0031.20214.01929.360-6.9011.0030.92213.80227.765-7.0431.0028.41214.97729.669-5.7561.0032.65215.01331.820—9.7511.0032.88216.16532.322-9.7011.0031.78224.33631.671-10.8961.0032.94224.84532.277-12.1581.0035.53223.90932.018-13.3611.0034.17224.41130.929-14.2281.0036.91224.29831.325-15.7171.0041.97225.32230.719-16.5821.0045.61225.85631.326-17.6541.0050.44225.45032.556-18.0031.0053.58226.77330.709-18.4141.0047.82225.03633.792-12.0571.0034,89225.97434.323-12.6311.0036.41234.16334.45911.3201.0034.39234.13535.907-11.2881.0035.20232.79836.309-10.9001.0032.57235.15936.557-10.3081.0036.77235.18337.791-10.1151.0037.27245.97535.729—9.6601.0036.97246.91936.211—8.6601.0035.80247.03135.065—7.6141.0036.41247.73335.453-6.3361.0038.68247.93133.997一5.2711.0042.38246.25233.503-5.1721.0025.09248.27236.529一9.3461.0034.67248.64535.857-10.2871.0036.83259.06937.505—8.9201.0033.232510.41437.652-9.5321.0032.182510.94639.098-9.3151.0031.822510,94439.337一7.9221.0029.962511.53836.710-9.0241.0031.792511.53536.265-7.9151.0033.622612.52936.444-9.8311.0031.122613.63535.679-9.3601.0032.442614.69735.588-10.3921.0031.902614.19136.273-8.0691.0033.652614.44135.549-7.1001.0032.562714.42137.588-8.0701.0034.162714.98838.277-6.8691.0033,652715.22439.858-7.1821.0033.672714.10138.072-5.6261.0033.432714.57737.908—4.5181.0035.18cNC0NCcc0NccccNcNNC0NCCcccc0NccccNcNNC0NCCC0NCccscc0Ncc0c0Nccc0Ncc:coAAAAAAAAAA八AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAASSSSAAAAAGGGGGGGGGGGUUUUUUUUGGGGGGGGGGGAAAAATTTEITTTTRRRRRRAAAAAAAAAA:IIIII"JIAAA;AAAAAAAAAAAAA:.LIJIII:-IIIIII.IIAAAAAAAAAAAAAAAAMMM::SMMM;MSSSSSSAAAAAAAAAA:121212EzABABGDEZHHABGDDABGDEZHHACDACDGD已ABGAB>ACD>CNCONCCCONCCCCNCNNCONCCCCCCONCCCCNCNNCONCCCONCCCSCCONCCOCONCCCONCCCOATOM196NGLUA2812.80638.092-5.7861.0032.39NATOM197CAGLUA2811.97037.973--4.6341.0031.78CATOM198CBGLUA2810.60038.361-5.0061.0031.37CATOM199CGGLUA289.51038.003-4.0301.0030.03cATOM200CDGLUA289.54838.775-2.6921.0034.21cATOM2010E1GLUA2810.37139.710-2.5911.0036.180扁M2020E2GLUA288.78138.445-1.7691.0032.050ATOMCGLUA2811.93736.506-4.1091.0032.05cATOM2040GLUA2811.95436.264-2.9291.0031.010ATOM205NALAA2911.83135.552-5.0041.0030.51NATOM206CAAL\A2911.87134.150-4.5861.0029.18cATOM207CBALAA2911.87333.274-5.8251.0027.80cATOM208CALAA2913.16633.971-3.7521.0029.50cATOM2090ALAA2913.16933.308-2.6981.0028.670ATOM210NLEUA3014.26334.557-4.2291.0029.16NATOM211CALEUA3015.55634.537-3.5291.0031.02cATOM212CBLEUA3016.67735.142-4.3671.0031.13cATOM213CGLEUA3017.21234.205-5.4431.0036.07cATOM214CD1LEUA3018.34034.894-6.3531.0038,83cATOM215CD2LEUA3017.66432.830_4.8401.0036.04cATOM216CLEUA3015.53235.205-2.1571.0031.09cATOM2170LEUA3016.19634.69-1.2281.0029.500ATOM218NARGA3114.77636.296-2.0281.0030.25NATOM219CAARGA3114.60036.986一O.7211.0031.05cATOM220CBARGA31IS-94238.338—0.8951.0031.74cATOM221CGARGA31IS.68039.0610.4421.0032.16cATOM222CDAKGA3112.91040.2830.1551.0031.47cATOM223NEARGA3111.51439.9480.1341.0029.35NATOM224CZARGA3110.84339.5691.1991.0033.31cATOM225NH1ARGA3111.47339.柳2.3801.0034.20NATOM226NH2ARGA319.55139.2581.0871.0030.62NATOM227CARGA3113.79836.1440.3421.0032.04CATOM2280ARGA3114.23136.0341.4921.0030.170ATOM229NGLNA3212.74935.448-O.0951.0027.97NATOM230CAGLNA3211.92734.7440.8371.0027.35CATOM231CBGLNA3210.54534.3380.2981.0026.37CATOM232CGGLNA329.54935.4090.2771.0026.39cATOM233CDGLNA328.18534.953-O.0351.0025.78cATOM2340E1GLNA327.60434.1150.6671.0028.340ATOM235NE2GLNA327.55035.636-1.0451.0028.13NATOM236CGUMA3212.70533.4681.1951.0026.02cATOM2370GLNA3212.52132.9812.3381.0024.800ATOM238NSERA3313.44432.9260.2211.0024.87NATOM239CASERA3314.29231.7480.4631.0024.29cATOM240CBSERA3314.94631.217-0.8151.0023.16cATOM241OGSEKA3313.90230.910_1.7421.0020.000ATOM242CSERA3315.37432.1031.51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0038.1901.0042.920〗.0051.4601.00肌6601.0042.5401.0050.5901.0064.2201.00肌9701.0046.4901.0056,2001.0036，8001.0047.6901.0048.8201,0042.89。1.0053.4701.0052.0501.0048.1001.0045.3301.0043.0901.0046.1401.0058.9401.0053.9001.0052，1201,0051.1201.0029.4601.0036.1201.0043.3901,0047,9701,0051.8601.0042.320-2345678901234567890123456789012345678901--777777778888888888999999999900000000001H1.5旧附附HHH555旧附HHHHHHH!HHHHHHHHHHHHHHHHHHHHHHHHH附M附W附S附附SS州S州SS州州州S州刑州州州OO000OO000O00O0000000OO000OO00O00O00O0O0OO0O0OO000O0O00O0000O02O0202HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH143各种MTHFS突变体以及人野生型MTHFS的酶活性测定通过对各种MTHFS同源蛋白的生物化学和酶学性质的研究，发明人挑选了15个位点进行定点突变研究。突变使用的原理是通过使用定点突变的方法将分析得到的潜在关键位点进行突变，突变的方法使用STRATAGENE公司定点突变试剂盒，通过PCR—步得到突变体，经过DNA测序来验证突变是否成功。潜在的关键氨基酸残基都被突变成为丙氨酸(A)，由于丙氨酸具有最简单的氨基酸支链，同时又对蛋白质的二级结构产生很小的影响，所以这一方法已经成为广泛用于定点突变中。以5-甲基四氢叶酸为底物，加入任一种MTHFS突变体或人野生型MTHFS以及辅助因子镁离子、ATP(三磷酸腺苷)。室温反应2分钟，通过紫外吸收光谱检测360nm处吸收光强度的变化，确定生成物5，10-亚甲基四氢叶酸的含量，进而确定酶活性的强弱。将人野生型MTHFS的活性设为100%，突变体酶的相对活性为与人野生型酶活性比较获得。表7.MTHFS突变体的相对活性<table>tableseeoriginaldocumentpage144</column></row><table>人源5，10-次甲基四氢叶酸合成酶及其复合物的空间构型<table>tableseeoriginaldocumentpage144</column></row><table>经结构修正得到人源MTHFS的原子坐标，MTHFS的三维结构见图3，其中该酶的三维结构中包括a螺旋和P片层，其位点如下a12-18;a226-42;a344-48;P150-54;a465-73;P277-84;P389-95;P4131-134;P5138-140;P6145-146;a5152-162;P7169-173;P8194-196。从突变实验以及三维结构图的结果可知以下几个位点对于酶发挥活性是关键的F55、M58、E61、M90、Y152、Y153通过与底物5-甲基四氢叶酸中的蝶呤基团结合来发挥酶活性；F85、W109、R148通过与底物5-甲基四氢叶酸中的对氨基苯甲酸基团结合来发挥酶活性；KIO、R14、R145、D154通过与ATP结合来发挥酶活性。人源5，10-次甲基四氢叶酸合成酶与ADP复合物蛋白结合磷酸基团以后，在结构中原来无法建模的部分，E187-D189，在人源MTHFS结合ADP的复合物结构中得到了很好的构建。E187-D189位于ATP的结合部位，D189与ATP水解下来的磷酸的01氧原子形成一个氢键，并且结合了一个镁离子。另外，D189和K10形成一个盐桥。这些新的化学作用键的形成，使得在脱辅基蛋白结构中无法建模的部分(A174-D193)得到了稳定。由于在三维结构中只能显示ADP的两个磷酸基团和一个从ATP上水解下来的磷酸基团，其中水解下来的磷酸将作为亲核基团参与酶反应。此磷酸基团位于a5(152-161位氨基酸)的一段，151-153位氨基酸残基与之有相互作用。使用ATP类似物，例如使用硫类似物来替代磷酸基团设计小分子药物可以抑制此处磷酸基团进入酶分子，从而抑制酶活性。人源5，10-次甲基四氢叶酸合成酶与谷氨酸复合物结合在一个111-116位氨基酸残基附近的中性电荷裂缝上，该裂缝为P3(89-95氨基酸区段)和134(131-135氨基酸区段)之间的一个大Loop环区域，其中G115和E116与它有4埃之内的相互作用，谷氨酸部分通过一个圆形口突出结合口袋以外而位于蛋白表面。这种特异性的结合可以被用来设计多肽抑制剂，用来设计特异性的酶抑制剂。人源5，10-次甲基四氢叶酸合成酶与N5-亚胺磷酸过渡态的复合物氨基酸残基F55，L56，S57，M58，E61，P81，Y83，M90，W109，P135，R148，K150，Y152和Y153围成的一个大球形口袋中，5-亚胺磷酸反应中间态的蝶呤环就位于球形的中间。4-螺旋和3、4-折叠，以及它们之间的长loop，形成了一个帽子形状的结构覆盖在活性中心的上面。W109位于蝶呤环的上面，并且看上去是用来关闭活性中心的盖子，W109与蝶呤环的距离为7A,说明两者之间没有相互作用。蝶呤环的构象并不是一个平面，它在C6位置沿垂直轴方向伸展。61位的羧基氧与蝶呤环的N3和氨基氮相互作用。E61在直系同源MTHFS中是保守残基。M90与蝶呤环的N8形成一个氢键。在蝶呤环和F55，Y83，P135，Y152，Y153的芳香侧链之间存在着很多疏水的范德华力相互作用。Y83在野生型和复合物的晶体中区别最大，Y83的侧链发生旋转形成一个垂直状态，使得蝶呤环进入结合口袋。Y83侧链的移动，反过来使Y85的侧链远离了结合口袋。所述的氨基酸残基均为参与酶反应的关键基团，可以为设计小分子药物提供结构信息。此N5-亚胺磷酸过渡态中，蝶呤环以C4a与C8a之间的键为轴发生了扭转，所述喋呤环上的电子发生了重排。人源5，10-次甲基四氢叶酸合成酶与生成物10-甲酰四氢叶酸的复合物与人源5，10-次甲基四氢叶酸合成酶与N5-亚胺磷酸过渡态的复合物空间的构型总体上相同，只有Y83侧链的移动位置不同。Y83可以用来设计抑制其移动的小分子，进而设计小分子药物。上面的结构信息可用于设计或制造药物。本发明还提供了5，10-次甲基四氢叶酸合成酶或其复合物的抑制剂，包括与上述的结构域类似或者与上述的结构域结合的小分子化合物、短肽、多肽、核酸、抗体或免疫结合物。本发明还提供了用于移植癌症的药物组合物，包括5，10-次甲基四氢叶酸合成酶或其复合物的抑制剂，以及药用载体或赋形物。序列表〈110〉中国科学院生物物理研究所〈120〉人源5，10-次甲基四氢叶酸合成酶及其复合物的结晶方法、晶体以及应用〈130〉P25377IBP〈160>1〈170>PatentInversion3.2〈210>1〈211>203〈212>PRT〈213〉人类〈400>1MetAlaAlaAlaAlaValSerSerAlaLysArgSerLeuArgGlyGlu151015LeuLysGinArgLeuArgAlaMetSerAlaGluGluArgLeuArgGin202530SerArgValLeuSerGinLysVallieAlaHisSerGluTyrGinLys354045SerLysArglieSerliePheLeuSerMetGinAspGlulieGluThr505560GluGlulielieLysAspliePheGinArgGlyLyslieCysPhelie65707580ProArgTyrArgPheGinSerAsnHisMetAspMetValArglieGlu859095SerProGluGlulieSerLeuLeuProLysThrSerTrpAsnliePro100105110GinProGlyGluGlyAspValArgGluGluAlaLeuSerThrGlyGly115120125LeuAspLeuliePheMetProGlyLeuGlyPheAspLysHisGlyAsn130135140ArgLeuGlyArgGlyLysGlyTyrTyrAspAlaTyrLeuLysArgCys145150155160LeuGinHisGinGluValLysProTyrThrLeuAlaLeuAlaPheLys165170175GluGinlieCysLeuGinValProValAsnGluAsnAspMetLysVal180185190AspGluValLeuTyrGluAspSerSerThrAla195200权利要求一种人源5，10-次甲基四氢叶酸合成酶的晶体，其特征在于所述晶体的空间群为C2221，晶胞参数为a＝48.70±2b＝145.12±2c＝59.21±2α＝90.00°，β＝90.00°，γ＝90.00°。F2009101344744C0000011.tif,F2009101344744C0000012.tif,F2009101344744C0000013.tif2.—种人源5，10-次甲基四氢叶酸合成酶与ADP的复合物的晶体，其特征在于所述晶体的空间群为C2221，晶胞参数为a=48.51±2A，b=145.22±2A，c=59.65±2A;a=90.00°，P=90.00°，y=90.00°。3.—种人源5，10-次甲基四氢叶酸合成酶与ADP的复合物的晶体，其特征在于所述晶体的空间群为P21212，晶胞参数为a=59.579±2A,b=144.101±2A，c=48.532±2A;a=90.00°，P=90.00°，y=90.00°。4.一种人源5，10-次甲基四氢叶酸合成酶与谷氨酸的复合物的晶体，其特征在于所述晶体的空间群为C2221，晶胞参数为a=48.45±2A,b=145.23±2A，c=59.60±2A;a=90.00°，=90.00°，y=90.00°。5.—种人源5，10-次甲基四氢叶酸合成酶与N5-亚胺磷酸过渡态的复合物的晶体，其特征在于所述晶体的空间群为C2221，晶胞参数为a=48.69±2A,b=141.03±2A,c=59.99±2人；a=90.00°，P=90.00°，y=90.00°。6.—种人源5，10-次甲基四氢叶酸合成酶与10-甲酰四氢叶酸的复合物的晶体，其特征在于所述晶体的空间群为C2221，晶胞参数为a=48.86±2A,b=144.97±2A,c=59.41±2人；a=90.00°，P=90.00°，y=90.00°。7.根据权利要求1所述的人源5，10-次甲基四氢叶酸合成酶的晶体的结晶方法，包括将所述人源5，10-次甲基四氢叶酸合成酶的溶液与池液混合；利用悬滴法或坐滴法进行结晶；在1-2天后收集晶体；其特征在于，在5至25摄氏度、50%至80%的湿度范围内，池液为含0.01-0.03mol/LMgCl2、0.01-0.04mol/LNiCl2、20%-30%PEG3000至4000、0.lmol/L的pH二6.4-7.0的N-2-羟乙基哌嗪-N-2-乙磺酸或吗啉乙磺酸缓冲液。8.根据权利要求2或3所述的人源5，10-次甲基四氢叶酸合成酶与ADP的复合物的晶体的结晶方法，包括向所述人源5，10-次甲基四氢叶酸合成酶的溶液中加入ATP溶液，再加入还原剂和镁离子，混合后得到人源5，10-次甲基四氢叶酸合成酶与ATP的混合液；将所述人源5，10-次甲基四氢叶酸合成酶与ATP的混合液与池液混合；利用悬滴法或坐滴法进行结晶；在1-2天后收集晶体；其特征在于，在5至25摄氏度、50%至80%的湿度范围内，池液为含0.01-0.03mol/LMgCl2、0.01-0.04mol/LNiCl2、20%-30%PEG3000至4000、0.lmol/L的pH二6.4-7.0的N-2-羟乙基哌嗪-N-2-乙磺酸或吗啉乙磺酸缓冲液。9.根据权利要求4所述的人源5，10-次甲基四氢叶酸合成酶与谷氨酸的复合物的晶体的结晶方法，包括向所述人源5，10-次甲基四氢叶酸合成酶的溶液中加入谷氨酸溶液，混合后得到人源5，10-次甲基四氢叶酸合成酶与谷氨酸的混合液；将所述人源5，10-次甲基四氢叶酸合成酶与谷氨酸的混合液与池液混合；利用悬滴法或坐滴法进行结晶；在1-2天后收集晶体；其特征在于，在5至25摄氏度、50%至80%的湿度范围内，池液为含0.01-0.03mol/LMgCl2、0.01-0.04mol/LNiCl2、20%-30%PEG3000至4000、0.lmol/L的pH二6.4-7.0的N-2-羟乙基哌嗪-N-2-乙磺酸或吗啉乙磺酸缓冲液。10.根据权利要求5所述的人源5，10-次甲基四氢叶酸合成酶与N5-亚胺磷酸过渡态的复合物的晶体的结晶方法，包括向所述人源5，10-次甲基四氢叶酸合成酶的溶液中加入ATP、5-甲酰四氢叶酸、巯基乙醇、镁离子溶液，混合后得到人源5，10-次甲基四氢叶酸合成酶与N5-亚胺磷酸的混合液；将所述人源5，10-次甲基四氢叶酸合成酶与N5-亚胺磷酸的混合液与池液混合；利用悬滴法或坐滴法进行结晶；在1-2天后收集晶体；其特征在于，在5至25摄氏度、50%至80%的湿度范围内，池液为含0.01-0.03mol/LMgCl2、0.01-0.04mol/LNiCl2、20%-30%PEG3000至4000、0.lmol/L的pH二6.4-7.0的N-2-羟乙基哌嗪-N-2-乙磺酸或吗啉乙磺酸缓冲液。11.根据权利要求6所述的人源5，10-次甲基四氢叶酸合成酶与10-甲酰四氢叶酸的复合物的晶体的结晶方法，包括向所述人源5，10-次甲基四氢叶酸合成酶的溶液中加入ATP、5-甲酰四氢叶酸、巯基乙醇、镁离子溶液，混合后得到人源5，10-次甲基四氢叶酸合成酶与N5-亚胺磷酸的混合液；将所述人源5，10-次甲基四氢叶酸合成酶与N5-亚胺磷酸的混合液与池液混合；利用悬滴法或坐滴法进行结晶；在4-14天后收集晶体；其特征在于，在5至25摄氏度、50%至80%的湿度范围内，池液为含0.01-0.03mol/LMgCl2、0.01-0.04mol/LNiCl2、20%-30%PEG3000至4000、0.lmol/L的pH二6.4-7.0的N-2-羟乙基哌嗪-N-2-乙磺酸或吗啉乙磺酸缓冲液。12.根据权利要求1所述的人源5，10-次甲基四氢叶酸合成酶的晶体的F55、M58、E61、190、￥152、￥153位氨基酸在空间中所形成的结构域，其特征在于所述结构域与底物5-甲酰四氢叶酸中的蝶呤基团结合。13.根据权利要求1所述的人源5，10-次甲基四氢叶酸合成酶的晶体的F85、W109、尺148位氨基酸在空间中所形成的结构域，其特征在于所述结构域与底物5-甲酰四氢叶酸中的对氨基苯甲酸基团结合。14.根据权利要求1所述的人源5，10-次甲基四氢叶酸合成酶的晶体的K10、R14、R145、D154位氨基酸在空间中所形成的结构域，其特征在于所述结构域与ATP结合。15.根据权利要求2所述的人源5，10-次甲基四氢叶酸合成酶与ADP的复合物的晶体中a5的152-161位氨基酸在空间中所形成的结构域，其特征在于所述结构域是与从ATP水解下来的磷酸基团结合的结构域。16.根据权利要求4所述的人源5，10-次甲基四氢叶酸合成酶与谷氨酸的复合物的晶体中|33和P4之间的氨基酸即第89和134位氨基酸之间的氨基酸在空间中所形成的结构域，其特征在于所述结构域形成一个loop环结构，该结构中的氨基酸与谷氨酸结合。17.根据权利要求5所述的人源5，10-次甲基四氢叶酸合成酶与N5-亚胺磷酸过渡态的复合物的晶体中氨基酸残基F55、L56、S57、M58、E61、P81、Y83、M90、W109、P135、R148、K150、Y152和Y153所形成的结构域，其特征在于所述结构域形成一个球形口袋，N5-亚胺磷酸过渡态的蝶呤环位于所述球形口袋的中间。18.根据权利要求5所述的人源5，10-次甲基四氢叶酸合成酶与N5-亚胺磷酸过渡态的复合物的晶体中蝶呤环在空间中的结构域，其特征在于所述蝶呤环以C4a与C8a之间的键为轴发生了扭转，所述喋呤环上的电子发生了重排。19.根据权利要求6所述的人源5，10-次甲基四氢叶酸合成酶与10-甲酰四氢叶酸的复合物的晶体中Y83在空间中的结构域，其特征在于Y83的位置与在权利要求5所述的晶体的位置相比，发生了变化。20.与权利要求12-19中任一项所述的结构域类似或者与所述结构域结合的小分子化合物、短肽、多肽、核酸、抗体或免疫结合物中的一种或几种的组合物。全文摘要本发明涉及一种人源5，10-次甲基四氢叶酸合成酶(MTHFS)的晶体及其结晶的方法，同时也涉及人源5，10-次甲基四氢叶酸合成酶与ADP的复合物的晶体及其结晶的方法、人源5，10-次甲基四氢叶酸合成酶与谷氨酸的复合物的晶体及其结晶的方法、人源5，10-次甲基四氢叶酸合成酶与N5-亚胺磷酸的复合物的晶体及其结晶的方法、人源5，10-次甲基四氢叶酸合成酶与产物10-甲酰四氢叶酸复合物的晶体及其结晶的方法；还涉及这些晶体中重要的结构域或肽片段；以及利用这些结构域或肽片段进行药物设计和筛选的方法。文档编号C07K16/40GK101781637SQ20091013447公开日2010年7月21日申请日期2009年4月17日优先权日2009年4月17日发明者刘志杰,宋高洁,尼尔·肖恩,成冲云,李杨,武栋申请人:中国科学院生物物理研究所