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HIV-1 reverse transcriptase complex with DNA and nevirapine reveals non-nucleoside inhibition mechanism.

<div class='caption-title'>Polymerase domain of HIV-1 RT in complex with DNA</div>
<div class='caption-title'>Effects of nevirapine on polymerase active site conformation and dNTP-binding</div>
<div class='caption-title'>Impact of nevirapine binding on thumb, fingers and DNA</div>
Das K, Martinez SE, Bauman JD, Arnold E
OpenAccess logo Nat Struct Mol Biol 19 253-9 (2012)
Related entries: 1rtd, 1s6p, 1s6q, 1s9e, 1s9g, 1suq, 1sv5, 2zd1, 2ze2, 3bgr, 3jsm, 3jyt, 3kle, 3klf, 3klg, 3klh, 3kli, 3v6d, 3v81

Cited: 109 times
EuropePMC logo PMID: 22266819

Abstract

Combinations of nucleoside and non-nucleoside inhibitors (NNRTIs) of HIV-1 reverse transcriptase (RT) 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, RT-DNA, and RT-DNA-AZT-triphosphate complexes at 2.85-, 2.70- and 2.80-Å resolution, respectively. The RT-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 ~5.5 Å 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.

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