Complexes of HIV-1 reverse transcriptase with inhibitors of the HEPT series reveal conformational changes relevant to the design of potent non-nucleoside inhibitors
Complexes of HIV-1 reverse transcriptase with inhibitors of the HEPT series reveal conformational changes relevant to the design of potent non-nucleoside inhibitors
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DOI：
10.1021/jm960056x
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发表时间：
1996-04-12
影响因子：
7.3
通讯作者：
Stuart, DI
中科院分区：
文献类型：
--
作者：
Hopkins, AL;Ren, JS;Stuart, DI
HIV-1逆转录酶（RT）与一系列化学上不同的非核苷抑制剂（NNI）复合的晶体结构显示了抑制剂结合的单个口袋和蛋白质相互作用的细节。为了描述有效抑制剂的结构要求，我们确定了三种密切相关的NNI的结构，这些NNI的效力差异很大。在2.55埃分辨率下，HIV-1 RT与两种非常有效的抑制剂MKC-442和TNK-651复合的晶体结构补充了我们先前对具有较低有效抑制剂HEPT的复合物的分析。这些结构揭示了与效价变化相关的构象变化。我们认为，在HEPT类似物的效力增加的一个主要决定因素是一个改进的残基Tyr 181在蛋白质和6-苄基环的抑制剂，稳定的复杂的结构之间的相互作用。这是通过抑制剂嘧啶环的5-取代基的空间体积触发的蛋白质结构的构象转换而产生的。
Crystal structures of HIV-1 reverse transcriptase (RT) complexed with a range of chemically diverse non-nucleoside inhibitors (NNIs) have shown a single pocket in which the inhibitors bind and details of the inhibitor-protein interactions. To delineate the structural requirements for an effective inhibitor, we have determined the structures of three closely related NNIs which vary widely in their potencies. Crystal structures of HIV-1 RT complexed with two very potent inhibitors, MKC-442 and TNK-651, at 2.55 Angstrom resolution complement our previous analysis of the complex with the less effective inhibitor, HEPT. These structures reveal conformational changes which correlate with changes in potency. We suggest that a major determinant of increased potency in the analogues of HEPT is an improved interaction between residue Tyr181 in the protein and the 6-benzyl ring of the inhibitors which stabilizes the structure of the complex. This arises through a conformational switching of the protein structure triggered by the steric bulk of the 5-substituent of the inhibitor pyrimidine ring.