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首页> 外文期刊>Acta crystallographica.Section D. Biological crystallography >Structural basis for drug and substrate specificity exhibited by FIV encoding a chimeric FIV/HIV protease.
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Structural basis for drug and substrate specificity exhibited by FIV encoding a chimeric FIV/HIV protease.

机译：药物和衬底结构依据FIV编码所展现出来的特异性嵌合体山区-艾滋病毒蛋白酶。

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摘要

A chimeric feline immunodeficiency virus (FIV) protease (PR) has been engineered that supports infectivity but confers sensitivity to the human immunodeficiency virus (HIV) PR inhibitors darunavir (DRV) and lopinavir (LPV). The 6s-98S PR has five replacements mimicking homologous residues in HIV PR and a sixth which mutated from Pro to Ser during selection. Crystal structures of the 6s-98S FIV PR chimera with DRV and LPV bound have been determined at 1.7 and 1.8 A resolution, respectively. The structures reveal the role of a flexible 90s loop and residue 98 in supporting Gag processing and infectivity and the roles of residue 37 in the active site and residues 55, 57 and 59 in the flap in conferring the ability to specifically recognize HIV PR drugs. Specifically, Ile37Val preserves tertiary structure but prevents steric clashes with DRV and LPV. Asn55Met and Val59Ile induce a distinct kink in the flap and a new hydrogen bond to DRV. Ile98Pro-->Ser and Pro100Asn increase 90s loop flexibility, Gln99Val contributes hydrophobic contacts to DRV and LPV, and Pro100Asn forms compensatory hydrogen bonds. The chimeric PR exhibits a comparable number of hydrogen bonds, electrostatic interactions and hydrophobic contacts with DRV and LPV as in the corresponding HIV PR complexes, consistent with IC(50) values in the nanomolar range.
机译：嵌合猫免疫缺陷病毒(fip)蛋白酶(PR)工程支持传染性,但所带来的对人类的敏感性免疫缺陷病毒(HIV)公关抑制剂内(DRV)和lopinavir (LPV)。公关有五个替代品模仿同源残留在艾滋病毒的公关和突变的六分之一箴Ser在选择。6 - 98年代FIV的公关嵌合体DRV和LPV已经确定在1.7和1.8分别解决。灵活的角色90年代98年循环和残渣支持Gag处理和传染性角色的残留活性部位和37残留55岁,57、59赋予的皮瓣专门识别艾滋病公关的能力药物。结构但是DRV防止空间冲突和LPV。扭结的皮瓣和一个新的氢键DRV。Ile98Pro——> Ser和90年代Pro100Asn增加循环灵活性,Gln99Val疏水联系人DRV和LPV Pro100Asn形式补偿氢键。展览将有相当数量的氢键,静电相互作用和疏水接触DRV和LPV在相应的艾滋病毒公关复合物,与集成电路(50)值一致在摩尔的范围内。

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