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dc.contributor.authorMartin, JL
dc.contributor.authorBegun, J
dc.contributor.authorSchindeler, A
dc.contributor.authorWickramasinghe, WA
dc.contributor.authorAlewood, D
dc.contributor.authorAlewood, PF
dc.contributor.authorBergman, DA
dc.contributor.authorBrinkworth, RI
dc.contributor.authorAbbenante, G
dc.contributor.authorMarch, DR
dc.contributor.authorReid, RC
dc.contributor.authorFairlie, DP
dc.date.accessioned2017-10-05T01:10:20Z
dc.date.available2017-10-05T01:10:20Z
dc.date.issued1999
dc.identifier.issn0006-2960
dc.identifier.doi10.1021/bi990174x
dc.identifier.urihttp://hdl.handle.net/10072/347878
dc.description.abstractHigh-resolution crystal structures are described for seven macrocycles complexed with HIV-1 protease (HIVPR). The macrocycles possess two amides and an aromatic group within 15−17 membered rings designed to replace N- or C-terminal tripeptides from peptidic inhibitors of HIVPR. Appended to each macrocycle is a transition state isostere and either an acyclic peptide, nonpeptide, or another macrocycle. These cyclic analogues are potent inhibitors of HIVPR, and the crystal structures show them to be structural mimics of acyclic peptides, binding in the active site of HIVPR via the same interactions. Each macrocycle is restrained to adopt a β-strand conformation which is preorganized for protease binding. An unusual feature of the binding of C-terminal macrocyclic inhibitors is the interaction between a positively charged secondary amine and a catalytic aspartate of HIVPR. A bicyclic inhibitor binds similarly through its secondary amine that lies between its component N-terminal and C-terminal macrocycles. In contrast, the corresponding tertiary amine of the N-terminal macrocycles does not interact with the catalytic aspartates. The amine−aspartate interaction induces a 1.5 Å N-terminal translation of the inhibitors in the active site and is accompanied by weakened interactions with a water molecule that bridges the ligand to the enzyme, as well as static disorder in enzyme flap residues. This flexibility may facilitate peptide cleavage and product dissociation during catalysis. Proteases [Aba67,95]HIVPR and [Lys7,Ile33,Aba67,95]HIVPR used in this work were shown to have very similar crystal structures.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherAmerican Chemical Society
dc.relation.ispartofpagefrom7978
dc.relation.ispartofpageto7988
dc.relation.ispartofissue25
dc.relation.ispartofjournalBiochemistry
dc.relation.ispartofvolume38
dc.subject.fieldofresearchMedicinal and biomolecular chemistry
dc.subject.fieldofresearchBiochemistry and cell biology
dc.subject.fieldofresearchBiochemistry and cell biology not elsewhere classified
dc.subject.fieldofresearchMedical biochemistry and metabolomics
dc.subject.fieldofresearchcode3404
dc.subject.fieldofresearchcode3101
dc.subject.fieldofresearchcode310199
dc.subject.fieldofresearchcode3205
dc.titleMolecular recognition of macrocyclic peptidomimetic inhibitors by HIV-1 protease
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
gro.hasfulltextNo Full Text
gro.griffith.authorMartin, Jennifer


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