HIV-1 reverse transcriptase complex with DNA and nevirapine reveals non-nucleoside inhibition mechanism
HIV-1 reverse transcriptase complex with DNA and nevirapine reveals non-nucleoside inhibition mechanism
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DOI：
10.1038/nsmb.2223
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发表时间：
2012-02-01
影响因子：
16.8
通讯作者：
Arnold, Eddy
中科院分区：
文献类型：
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作者：
Das, Kalyan;Martinez, Sergio E.;Arnold, Eddy
HIV-1逆转录酶(RI)的核苷和非核苷抑制剂(NNRTI)的组合在抗艾滋病治疗中被广泛使用。包括奈韦拉平在内的5种NNRTI是临床药物；然而，NNRTI抑制的分子机制尚不清楚。我们测定了RT-DNA-奈韦拉平、RI-DNA和RT-DNA-AZT-三磷酸配合物在2.85埃、2.70埃和2.80埃分辨率下的晶体结构。晶体中的RI-DNA复合体可以与奈韦拉平或AZT-三磷酸结合，但不能同时与两者结合。奈韦拉平的结合导致NNRTI结合口袋的打开。口袋的形成导致DNA引物的3‘端偏离其聚合酶活性位置约5.5埃。与手指和手掌亚区的核酸相互作用减少，dNTP结合口袋扭曲，拇指张开。这些结构阐明了核苷和非核苷抑制剂在抑制RT方面的互补作用。
Combinations of nucleoside and non-nucleoside inhibitors (NNRTIs) of HIV-1 reverse transcriptase (RI) are widely used in anti-AIDS therapies. Five NNRTIs, including nevirapine, are clinical drugs; however, the molecular mechanism of inhibition by NNRTIs is not clear. We determined the crystal structures of RT-DNA-nevirapine, RI-DNA, and RT-DNA-AZT-triphosphate complexes at 2.85-, 2.70- and 2.80-angstrom resolution, respectively. The RI-DNA complex in the crystal could bind nevirapine or AZT-triphosphate but not both. Binding of nevirapine led to opening of the NNRTI-binding pocket. The pocket formation caused shifting of the 3' end of the DNA primer by similar to 5.5 angstrom away from its polymerase active site position. Nucleic acid interactions with fingers and palm subdomains were reduced, the dNTP-binding pocket was distorted and the thumb opened up. The structures elucidate complementary roles of nucleoside and non-nucleoside inhibitors in inhibiting RT.