title: X-ray crystallographic structure of a complex between a synthetic protease of human immunodeficiency virus 1 and a substrate-based hydroxyethylamine inhibitor.
abstract: The structure of a crystal complex of the chemically synthesized protease of human immunodeficiency virus 1 with a heptapeptide-derived inhibitor bound in the active site has been determined. The sequence of the inhibitor JG-365 is Ac-Ser-Leu-Asn-Phe-psi[CH(OH)CH2N]-Pro-Ile-Val-OMe; the Ki is 0.24 nM. The hydroxyethylamine moiety, in place of the normal scissile bond of the substrate, is believed to mimic a tetrahedral reaction intermediate. The structure of the complex has been refined to an R factor of 0.146 at 2.4-A resolution by using restrained least squares with rms deviations in bond lengths of 0.02 A and bond angles of 4. The bound inhibitor diastereomer has the S configuration at the hydroxyethylamine chiral carbon, and the hydroxyl group is positioned between the active site aspartate carboxyl groups within hydrogen bonding distance. Comparison of this structure with a reduced peptide bond inhibitor-protease complex indicates that these contacts confer the exceptional binding strength of JG-365.
authors: Crystallography Laboratory, National Cancer Institute-Frederick Cancer Research and Development Center, MD 21702.
authors: A L
authors: AL
authors: Swain
authors: M M
authors: MM
authors: Miller
authors: J
authors: J
authors: Green
authors: D H
authors: DH
authors: Rich
authors: J
authors: J
authors: Schneider
authors: S B
authors: SB
authors: Kent
authors: A
authors: A
authors: Wlodawer
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D003461:Crystallography; D015195:Drug Design; D017320:HIV Protease Inhibitors; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry*; D011480:Protease Inhibitors / Q000737:chemistry*; D011487:Protein Conformation; D014961:X-Ray Diffraction
chemical_list: D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011480:Protease Inhibitors; C066511:JG 365