title: Three-dimensional structure of a simian immunodeficiency virus protease/inhibitor complex. Implications for the design of human immunodeficiency virus type 1 and 2 protease inhibitors.
abstract: Simian immunodeficiency virus (SIV) proteins have considerable amino acid sequence homology to those from human immunodeficiency virus (HIV); thus monkeys are considered useful models for the preclinical evaluation of acquired immune deficiency syndrome (AIDS) therapeutics. We have crystallized and determined the three-dimensional structure of SIV protease bound to the hydroxyethylene isostere inhibitor SKF107457. Crystals of the complex were grown from 25-32% saturated sodium chloride, by the hanging drop method of vapor diffusion. They belong to the orthorhombic space group I222, with a = 46.3 A, b = 101.5 A, and c = 118.8 A. The structure has been determined at 2.5-A resolution by molecular replacement and refined to a crystallographic discrepancy factor, R (= sigma parallel Fo magnitude of - magnitude of Fc parallel/sigma magnitude of Fo magnitude of), of 0.189. The overall structure of the complex is very similar to previously reported structures of HIV-1 protease bound to inhibitors. The inhibitor is bound in a conformation that is almost identical to that found for the same inhibitor bound to HIV-1 protease, except for an overall translation of the inhibitor, varying along the backbone atoms from about 1.0 A at the termini to about 0.5 A around the scissile bond surrogate. The structures of the SIV and HIV-1 proteins vary significantly only in three surface loops composed of amino acids 15-20, 34-45, and 65-70. Superposition of the 1188 protein backbone atoms from the two structures gives an rms deviation of 1.0 A; this number is reduced to 0.6 A when atoms from the three surface loops are eliminated from the rms calculation.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Macromolecular Sciences, SmithKline Beecham, King of Prussia, Pennsylvania 19406.
authors.forename: B
authors.initials: B
authors.lastname: Zhao
authors.forename: E
authors.initials: E
authors.lastname: Winborne
authors.forename: M D
authors.initials: MD
authors.lastname: Minnich
authors.forename: J S
authors.initials: JS
authors.lastname: Culp
authors.forename: C
authors.initials: C
authors.lastname: Debouck
authors.forename: S S
authors.initials: SS
authors.lastname: Abdel-Meguid
mesh_terms: D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000737:chemistry; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000648:ultrastructure*; D018360:Crystallography, X-Ray; D017320:HIV Protease Inhibitors / Q000737:chemistry; D006860:Hydrogen Bonding; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000494:pharmacology; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015302:Simian Immunodeficiency Virus / Q000201:enzymology*
chemical_list: D000998:Antiviral Agents; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011994:Recombinant Proteins; C077943:SKF 107457; D016282:Aspartic Acid Endopeptidases; C077164:SIV(mac) proteinase