Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 5, Pages 1466-1471Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0711209105
Keywords
drug design; drug resistance; nonnucleoside reverse transcriptase inhibitor; polymerase; x-ray crystallography
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Funding
- Intramural NIH HHS Funding Source: Medline
- NIAID NIH HHS [R37 AI027690, AI 27690, R37 AI027690-20] Funding Source: Medline
- NIGMS NIH HHS [P01 GM066671-05, P01 GM 066671, P01 GM066671] Funding Source: Medline
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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 (similar to 25-75 mg/day). We have determined the structure of wild-type HIV-1 RT complexed with TMC278 at 1.8 angstrom 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 angstrom) and L1001/K103N HIV-1 RTs (2.9 angstrom) demonstrated that TMC278 adapts to bind mutant RTs. In the K103N/Y181C RT/TMC278 structure, loss of the aromatic ring interaction caused by the Y181C mutation is counterbalanced by interactions between the cyanovinyl group of TMC278 and the aromatic side chain of Y183, which is facilitated by an similar to 1.5 angstrom shift of the conserved Y183MDD motif. In the L1001/K103N RT/TMC278 structure, the binding mode of TMC278 is significantly altered so that the drug conforms to changes in the binding pocket primarily caused by the L1001 mutation. The flexible binding pocket acts as a molecular shrink wrap that makes a shape complementary to the optimized TMC278 in wild-type and drug-resistant forms of HIV-1 RT. The crystal structures provide a better understanding of how the flexibility of an inhibitor can compensate for drug-resistance mutations.
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