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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.

Type

Journal article

Journal

Structure

Publication Date

15/10/2000

Volume

8

Pages

1089 - 1094

Keywords

Amino Acid Substitution, Anti-HIV Agents, Benzoxazines, Binding Sites, Crystallography, X-Ray, Drug Resistance, Microbial, HIV Reverse Transcriptase, HIV-1, Humans, Models, Molecular, Mutation, Nevirapine, Oxazines, Protein Binding, Protein Conformation, Reverse Transcriptase Inhibitors, Structure-Activity Relationship