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

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.

• Authors: Kalyan Das, Sergio E Martinez, Joseph D Bauman, Eddy Arnold
• Journal: Nature structural & molecular biology (Nat Struct Mol Biol) Vol. 19 Issue 2 Pg. 253-9 (Jan 22 2012) ISSN: 1545-9985 [Electronic] United States
• PMID: 22266819 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Anti-HIV Agents
• DNA, Viral
• Nevirapine
• reverse transcriptase, Human immunodeficiency virus 1
• HIV Reverse Transcriptase

Topics

• Anti-HIV Agents (chemistry, metabolism)
• Crystallography, X-Ray
• DNA, Viral (chemistry, metabolism)
• HIV Reverse Transcriptase (antagonists & inhibitors, chemistry, metabolism)
• Models, Molecular
• Nevirapine (chemistry, metabolism)
• Nucleic Acid Conformation
• Protein Binding
• Protein Conformation