title: 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.affiliation: Center for Advanced Biotechnology and Medicine, Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey, USA.
authors.forename: Kalyan
authors.initials: K
authors.lastname: Das
authors.forename: Sergio E
authors.initials: SE
authors.lastname: Martinez
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Bauman
authors.forename: Eddy
authors.initials: E
authors.lastname: Arnold
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D004279:DNA, Viral / Q000737:chemistry* / Q000378:metabolism*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D019829:Nevirapine / Q000737:chemistry* / Q000378:metabolism*; D009690:Nucleic Acid Conformation; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D019380:Anti-HIV Agents; D004279:DNA, Viral; D019829:Nevirapine; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase