比较两个独立的人类二氢叶酸还原酶的晶体结构的三元复合物减少烟酰胺腺嘌呤二核苷酸磷酸和紧束缚抑制剂PT523。
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科迪V, Galitsky N,勒夫特小,Pangborn W, Rosowsky, Blakley RL
比较两个独立的人类二氢叶酸还原酶的晶体结构的三元复合物减少烟酰胺腺嘌呤二核苷酸磷酸和紧束缚抑制剂PT523。
生物化学。1997年11月11日,36 (45):13897 - 903。
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9374868 (在PubMed]
- 文摘
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两个独立的晶体结构数据形式(单斜C2,斜方晶系的P2(1) 2(1) 2(1)的三元复杂有效的抗肿瘤剂PT523 [Nα- (4-amino-4-deoxypteroyl) - N delta-hemiphthaloyl-L-ornithine],还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)和重组人类二氢叶酸还原酶(hDHFR)显示多个绑定取向hemiphthaloyl集团的抑制剂。分析这些数据表明PT523结合蝶啶环在同一方向观察甲氨蝶呤(MTX)类似物。然而,在每一个hemiphthaloyl环结构,占地三个不同的构象。C2晶格,phthaloyl一部分结合在两个扩展构象,A和C,每个构象异构体都有一个180度翻转o-carboxylate集团和第三,较低的入住率构象异构体B, phthaloyl组折叠在接触的活性部位的口袋里。斜方晶系的晶格,PT523 phthaloyl集团也有三个矫形器;然而,这些不同于单斜晶体的晶格中所观察到。A和C,两个主要的矫形器是流离失所的两侧的扩展位置观察到C2晶格,附近一个折叠构象异构体的C2晶格和其他扩展。这些矫形器形成更紧密的分子间接触比C2晶格。折叠构象异构体B是远离活性部位的一个独特的位置。也有显著差异的构象adenine-ribose一半NADPH的复合物,不同于其他inhibitor-NADPH-hDHFR三元复合物。 These data suggest that the added intermolecular contacts made by the hemiphaloyl group of PT523 contribute to its tighter binding to hDHFR than MTX, which does not extend as far from the active site and cannot make these contacts. These crystallographic observations of multiple conformations for the hemiphthaloyl group are in general agreement with solution NMR data for the binding of PT523 to hDHFR [Johnson et al. (1997) Biochemistry 36, 4399-4411], which show that the hemiphthaloyl group may adopt more than one conformation. However, the crystallographic data reveal more discretely occupied positions than can be interpreted from the solution data. These results suggest that crystal packing interactions may influence their stability.