Proceedings of the National Academy of Sciences · 1998 · 55 citations · 27 references
Life SciencesBiochemistryMolecular BiologyEnzymologyMolecular VirologyVirologyAntiviral AgentsAntiviral PharmacologyEnzyme InhibitionLigand BindingProtein StructureViral StructureAntiviral Structure-activity RelationshipsIntegrase ProteinsLysine-targeted InhibitorsMolecular Docking Of InhibitorsNucleotide Binding DomainsNucleotide-binding MotifProtein Backbone Hydrogen BondsViral Replication Control
HIV-1 integrase is essential for viral replication and can be inhibited by antiviral nucleotides. Photoaffinity labeling with the 3'-azido-3'-deoxythymidine (AZT) analog 3',5-diazido-2', 3'-dideoxyuridine 5'-monophosphate (5N3-AZTMP) and proteolytic mapping identified the amino acid 153-167 region of integrase as the site of photocrosslinking. Docking of 5N3-AZTMP revealed the possibility for strong hydrogen bonds between the inhibitor and lysines 156, 159, and 160 of the enzyme. Mutation of these residues reduced photocrosslinking selectively. This report elucidates the binding site of a nucleotide inhibitor of HIV-1 integrase, and possibly a component of the enzyme polynucleotide binding site.
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Frederic D. Bushman, Alan Engelman, Ira Palmer et al. · Proceedings of the National Academy of Sciences · 1993 · 349 citations