title: Molecular recognition of macrocyclic peptidomimetic inhibitors by HIV-1 protease.
abstract: High-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 beta-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 A 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.
authors.affiliation: Centre for Drug Design and Development, University of Queensland, Brisbane QLD 4072, Australia. j.martin@mailbox.uq.edu.au
authors.forename: J L
authors.initials: JL
authors.lastname: Martin
authors.forename: J
authors.initials: J
authors.lastname: Begun
authors.forename: A
authors.initials: A
authors.lastname: Schindeler
authors.forename: W A
authors.initials: WA
authors.lastname: Wickramasinghe
authors.forename: D
authors.initials: D
authors.lastname: Alewood
authors.forename: P F
authors.initials: PF
authors.lastname: Alewood
authors.forename: D A
authors.initials: DA
authors.lastname: Bergman
authors.forename: R I
authors.initials: RI
authors.lastname: Brinkworth
authors.forename: G
authors.initials: G
authors.lastname: Abbenante
authors.forename: D R
authors.initials: DR
authors.lastname: March
authors.forename: R C
authors.initials: RC
authors.lastname: Reid
authors.forename: D P
authors.initials: DP
authors.lastname: Fairlie
mesh_terms: D000613:Aminobutyrates / Q000737:chemistry; D001216:Asparagine / Q000737:chemistry; D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D015497:HIV-1 / Q000201:enzymology*; D007532:Isoleucine / Q000737:chemistry; D007930:Leucine / Q000737:chemistry; D008239:Lysine / Q000737:chemistry; D008958:Models, Molecular; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000737:chemistry; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry*; D010649:Phenylalanine / Q000737:chemistry; D011487:Protein Conformation; D013237:Stereoisomerism; D014633:Valine / Q000737:chemistry
chemical_list: D000613:Aminobutyrates; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D010456:Peptides, Cyclic; D007532:Isoleucine; C066511:JG 365; D010649:Phenylalanine; D001216:Asparagine; D007930:Leucine; D014633:Valine; D008239:Lysine