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

Nat Struct Mol Biol. 2012 Jan 22;19(2):253-9. doi: 10.1038/nsmb.2223.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

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


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

Associated data

  • PDB/3V4I
  • PDB/3V6D
  • PDB/3V81