High-resolution structures of HIV-1 reverse transcriptase/TMC278 complexes: strategic flexibility explains potency against resistance mutations.

ABSTRACT: TMC278 is a diarylpyrimidine (DAPY) nonnucleoside reverse transcriptase inhibitor (NNRTI) that is highly effective in treating wild-type and drug-resistant HIV-1 infections in clinical trials at relatively low doses ( approximately 25-75 mg/day). We have determined the structure of wild-type HIV-1 RT complexed with TMC278 at 1.8 A resolution, using an RT crystal form engineered by systematic RT mutagenesis. This high-resolution structure reveals that the cyanovinyl group of TMC278 is positioned in a hydrophobic tunnel connecting the NNRTI-binding pocket to the nucleic acid-binding cleft. The crystal structures of TMC278 in complexes with the double mutant K103N/Y181C (2.1 A) and L100I/K103N HIV-1 RTs (2.9 A) demonstrated that TMC278 adapts to bind mutant RTs. In the K103N/Y181C RT/TMC278 s

SUBMITTER: Das K 

PROVIDER: S-EPMC2234167 | biostudies-literature | 2008 Feb

REPOSITORIES: biostudies-literature