MECHANISM OF INHIBITION OF HIV-1 REVERSE-TRANSCRIPTASE BY NONNUCLEOSIDE INHIBITORS
MECHANISM OF INHIBITION OF HIV-1 REVERSE-TRANSCRIPTASE BY NONNUCLEOSIDE INHIBITORS
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DOI：
10.1038/nsb0495-303
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发表时间：
1995-04-01
期刊：
影响因子：
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通讯作者：
STUART, D
中科院分区：
文献类型：
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作者：
ESNOUF, R;REN, JS;STUART, D
未结合配体的HIV - 1逆转录酶的结构已在2.35埃分辨率下测定，并精修至R因子为0.219（对于所有数据），且具有良好的立体化学性质。未结合配体的结构是通过从预先生长的晶体中浸出一种弱结合的非核苷类抑制剂（HEPT）而获得的。与四种不同的逆转录酶和非核苷类抑制剂复合物的结构进行比较后发现，仅发生了微小的结构域重排，但在p66亚基（包含催化天冬氨酸残基110、185和186）中，一个三股β - 折叠相对于聚合酶位点的其余部分发生了显著的重新定位。这表明非核苷类抑制剂通过将聚合酶活性位点锁定在无活性构象来抑制逆转录酶，这让人联想到在无活性的p51亚基中观察到的构象。
The structure of unliganded HIV-1 reverse transcriptase has been determined at 2.35 Angstrom resolution and refined to an R-factor of 0.219 (for all data) with good stereochemistry. The unliganded structure was produced by soaking out a weak binding non-nucleoside inhibitor, HEPT, from pregrown crystals. Comparison with the structures of four different RT and non-nucleoside inhibitor complexes reveals that only minor domain rearrangements occur, but there is a significant repositioning of a three-stranded beta-sheet in the p66 subunit (containing the catalytic aspartic acid residues 110, 185 and 186) with respect to the rest of the polymerase site. This suggests that NNIs inhibit RT by locking the polymerase active site in an inactive conformation, reminiscent of the conformation observed in the inactive p51 subunit.