Molecular recognition of macrocyclic peptidomimetic inhibitors by HIV-1 protease

Martin, J. L., Begun, J., Schindeler, A., Wickramasinghe, W. A., Alewood, D., Alewood, P. F., Bergman, D. A., Brinkworth, R. I., Abbenante, G., March, D. R., Reid, R. C., Fairlie, D. P. and Armstrong, Richard A. (1999) Molecular recognition of macrocyclic peptidomimetic inhibitors by HIV-1 protease. Biochemistry, 38 25: 7978-7988. doi:10.1021/bi990174x

Author Martin, J. L.
Begun, J.
Schindeler, A.
Wickramasinghe, W. A.
Alewood, D.
Alewood, P. F.
Bergman, D. A.
Brinkworth, R. I.
Abbenante, G.
March, D. R.
Reid, R. C.
Fairlie, D. P.
Armstrong, Richard A.
Title Molecular recognition of macrocyclic peptidomimetic inhibitors by HIV-1 protease
Journal name Biochemistry   Check publisher's open access policy
ISSN 0006-2960
Publication date 1999-01-01
Year available 1999
Sub-type Article (original research)
DOI 10.1021/bi990174x
Open Access Status Not yet assessed
Volume 38
Issue 25
Start page 7978
End page 7988
Total pages 11
Place of publication Washington DC
Publisher American Chemical Society
Language eng
Subject C1
060107 Enzymes
060112 Structural Biology (incl. Macromolecular Modelling)
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 P-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 Angstrom 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 [Aba(67,95)]HIVPR and [Lys(7),Ile(33),Aba(67,95)]- HIVPR used in this work were shown to have very similar crystal structures.
Keyword Biochemistry & Molecular Biology
Immunodeficiency Virus Protease
Crystallographic Structure
Q-Index Code C1
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
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Created: Mon, 13 Aug 2007, 21:13:40 EST