High-resolution structures of HIV-1 reverse transcriptase/TMC278 complexes: Strategic flexibility explains potency against resistance mutations
| Autor: | Kalyan Das, Stephen H. Hughes, Joseph D. Bauman, Eddy Arnold, Aaron J. Shatkin, Arthur D. Clark, Yulia Volovik Frenkel, Paul J. Lewi |
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| Rok vydání: | 2008 |
| Předmět: |
Anti-HIV Agents
Protein Conformation Stereochemistry Amino Acid Motifs Molecular Sequence Data Mutant Crystallography X-Ray Protein Engineering chemistry.chemical_compound Protein structure Drug Resistance Viral Nitriles Hydrolase medicine Humans Amino Acid Sequence Enzyme Inhibitors Polymerase Diarylpyrimidines Multidisciplinary biology Reverse-transcriptase inhibitor Rilpivirine virus diseases Protein engineering Biological Sciences HIV Reverse Transcriptase Reverse transcriptase Pyrimidines chemistry Drug Design Mutation biology.protein Reverse Transcriptase Inhibitors medicine.drug |
| Zdroj: | Proceedings of the National Academy of Sciences. 105:1466-1471 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.0711209105 |
| Popis: | 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 (∼25–75 mg/day). We have determined the structure of wild-type HIV-1 RT complexed with TMC278 at 1.8 Å 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 Å) and L100I/K103N HIV-1 RTs (2.9 Å) 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 ∼1.5 Å shift of the conserved Y 183 MDD motif. In the L100I/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 L100I 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. |
| Databáze: | OpenAIRE |
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