1B6K

HIV-1 PROTEASE COMPLEXED WITH MACROCYCLIC PEPTIDOMIMETIC INHIBITOR 5

Summary for 1B6K

• Entry DOI: 10.2210/pdb1b6k/pdb
• Related: 1B6J 1B6L 1B6M 1B6N 1B6O 1B6P
• Descriptor: RETROPEPSIN, SULFATE ION, N-[3-(8-SEC-BUTYL-7,10-DIOXO-2-OXA-6,9-DIAZA-BICYCLO[11.2.2]HEPTADECA-1(16),13(17),14- TRIEN-11-YLAMINO)-2-HYDROXY-1-(4-HYDROXY-BENZYL)-PROPYL]-3-METHYL-2- (2-OXO-PYRROLIDIN-1-YL)-BUTYRAMIDE, ... (4 entities in total)
• Functional Keywords: complex (acid proteinase-peptide), hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Human immunodeficiency virus 1
• Cellular location: Matrix protein p17: Virion (Potential). Capsid protein p24: Virion (Potential). Nucleocapsid protein p7: Virion (Potential). Reverse transcriptase/ribonuclease H: Virion (Potential). Integrase: Virion (Potential): P03369
• Total number of polymer chains: 2
• Total formula weight: 22499.41

Authors

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. (deposition date: 1999-01-17, release date: 2000-01-07, Last modification date: 2023-11-15)

Primary citation

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.
Molecular recognition of macrocyclic peptidomimetic inhibitors by HIV-1 protease.
Biochemistry, 38:7978-7988, 1999

PubMed 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.

PubMed: 10387041
DOI: 10.1021/bi990174x

Experimental method

X-RAY DIFFRACTION (1.85 Å)