Crystal structures of HIV-1 reverse transcriptases mutated at codons 100, 106 and 108 and mechanisms of resistance to non-nucleoside inhibitors
| Autor: | Kurt Weaver, C.E. Nichols, P.P. Chamberlain, Steven A. Short, Jingshan Ren, David K. Stammers |
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| Jazyk: | angličtina |
| Rok vydání: | 2004 |
| Předmět: |
Models
Molecular Nevirapine Anti-HIV Agents Protein Conformation DNA polymerase Molecular Sequence Data Mutant Drug resistance Crystallography X-Ray medicine.disease_cause Structural Biology medicine Humans Binding site Codon Molecular Biology Mutation Binding Sites Molecular Structure biology Chemistry Virology Molecular biology HIV Reverse Transcriptase Reverse transcriptase biology.protein Reverse Transcriptase Inhibitors Nucleoside medicine.drug |
| Zdroj: | Journal of molecular biology. 336(3) |
| ISSN: | 1089-8638 0022-2836 |
| Popis: | Leu100Ile, Val106Ala and Val108Ile are mutations in HIV-1 reverse transcriptase (RT) that are observed in the clinic and give rise to resistance to certain non-nucleoside inhibitors (NNRTIs) including the first-generation drug nevirapine. In order to investigate structural mechanisms of resistance for different NNRTI classes we have determined six crystal structures of mutant RT-inhibitor complexes. Val108 does not have direct contact with nevirapine in wild-type RT and in the RT(Val108Ile) complex the biggest change observed is at the distally positioned Tyr181 which is > 8 A from the mutation site. Thus in contrast to most NNRTI resistance mutations RT(Val108Ile) appears to act via an indirect mechanism which in this case is through alterations of the ring stacking interactions of the drug particularly with Tyr181. Shifts in side-chain and inhibitor positions compared to wild-type RT are observed in complexes of nevirapine and the second-generation NNRTI UC-781 with RT(Leu100Ile) and RT(Val106Ala), leading to perturbations in inhibitor contacts with Tyr181 and Tyr188. Such perturbations are likely to be a factor contributing to the greater loss of binding for nevirapine compared to UC-781 as, in the former case, a larger proportion of binding energy is derived from aromatic ring stacking of the inhibitor with the tyrosine side-chains. The differing resistance profiles of first and second generation NNRTIs for other drug resistance mutations in RT may also be in part due to this indirect mechanism. |
| Databáze: | OpenAIRE |
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