1fko
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CRYSTAL STRUCTURE OF NNRTI RESISTANT K103N MUTANT HIV-1 REVERSE TRANSCRIPTASE IN COMPLEX WITH DMP-266(EFAVIRENZ)
OverviewOverview
BACKGROUND: Efavirenz is a second-generation non-nucleoside inhibitor of, HIV-1 reverse transcriptase (RT) that has recently been approved for use, against HIV-1 infection. Compared with first-generation drugs such as, nevirapine, efavirenz shows greater resilience to drug resistance, mutations within HIV-1 RT. In order to understand the basis for this, resilience at the molecular level and to help the design of, further-improved anti-AIDS drugs, we have determined crystal structures of, efavirenz and nevirapine with wild-type RT and the clinically important, K103N mutant. RESULTS: The relatively compact efavirenz molecule binds, as, expected, within the non-nucleoside inhibitor binding pocket of RT. There, are significant rearrangements of the drug binding site within the mutant, RT compared with the wild-type enzyme. These changes, which lead to the, repositioning of the inhibitor, are not seen in the interaction with the, first-generation drug nevirapine. CONCLUSIONS: The repositioning of, efavirenz within the drug binding pocket of the mutant RT, together with, conformational rearrangements in the protein, could represent a general, mechanism whereby certain second-generation non-nucleoside inhibitors are, able to reduce the effect of drug-resistance mutations on binding potency.
About this StructureAbout this Structure
1FKO is a Protein complex structure of sequences from Human immunodeficiency virus 1 with EFZ as ligand. Active as RNA-directed DNA polymerase, with EC number 2.7.7.49 Full crystallographic information is available from OCA.
ReferenceReference
Structural basis for the resilience of efavirenz (DMP-266) to drug resistance mutations in HIV-1 reverse transcriptase., Ren J, Milton J, Weaver KL, Short SA, Stuart DI, Stammers DK, Structure. 2000 Oct 15;8(10):1089-94. PMID:11080630
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