Structure of the protease from simian immunodeficiency virus: complex with an irreversible nonpeptide inhibitor. NLM AIDSLINE Important note: Information in this article was accurate in 1994. The state of the art may have changed since the publication date.

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Structure of the protease from simian immunodeficiency virus: complex with an irreversible nonpeptide inhibitor.

Biochemistry. 1993 Nov 23;32(46):12498-507. Unique Identifier : AIDSLINE MED/94059962
Rose RB; Rose JR; Salto R; Craik CS; Stroud RM; Department of Biochemistry, University of California at San; Francisco 94143-0448.

Abstract: A variant of the simian immunodeficiency virus protease (SIV PR), covalently bound to the inhibitor 1,2-epoxy-3-(p-nitrophenoxy)propane (EPNP), was crystallized. The structure of the inhibited complex was determined by X-ray crystallography to a resolution of 2.4 A and refined to an R factor of 19%. The variant, SIV PR S4H, was shown to diminish the rate of autolysis by at least 4-fold without affecting enzymatic parameters. The overall root mean square (rms) deviation of the alpha-carbons from the structure of HIV-1PR complexed with a peptidomimetic inhibitor (7HVP) was 1.16 A. The major differences are concentrated in three surface loops with rms differences between 1.2 and 2.1 A. For 60% of the molecule the rms deviation was only 0.6 A. The structure reveals one molecule of EPNP bound per protease dimer, a stoichiometry confirmed by mass spectral analysis. The epoxide moiety forms a covalent bond with either of the active site aspartic acids of the dimer, and the phenyl moiety occupies the P1 binding site. The EPNP nitro group interacts with Arg 8. This structure suggests a starting template for the design of nonpeptide-based irreversible inhibitors of the SIV and related HIV-1 and HIV-2 PRs.
Keywords: Aspartic Acid/CHEMISTRY Aspartic Proteinases/*ANTAGONISTS & INHIB/ULTRASTRUCTURE Binding Sites Crystallography, X-Ray Epoxy Compounds/PHARMACOLOGY Nitrophenols/*PHARMACOLOGY Protein Structure, Secondary Protein Structure, Tertiary Recombinant Proteins Support, Non-U.S. Gov't Support, U.S. Gov't, P.H.S. SIV/*ENZYMOLOGY Water/CHEMISTRY JOURNAL ARTICLEKWDasparticacid/chemistryasparticproteinases/KWDantagonists&inhib/ultrastructurebindingsitescrystallography,x-rayepoxycompounds/pharmacologynitrophenols/KWDpharmacologyproteinstructure,secondaryproteinstructure,tertiaryrecombinantproteinssupport,non-uKWDsKWDgov'tsupport,uKWDsKWDgov't,pKWDhKWDsKWDsiv/KWDenzymologywater/chemistryjournalarticle
940330
M9430967

Copyright © 1994 - National Library of Medicine. Reproduced under license with the National Library of Medicine, Bethesda, MD.

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