STRUCTURE OF THE PROTEASE FROM SIMIAN IMMUNODEFICIENCY VIRUS - COMPLEX WITH AN IRREVERSIBLE NONPEPTIDE INHIBITOR

A variant of the simian immunodeficiency virus protease (SIV PR), cova lently bound to the inhibitor 1,2-epoxy-3-(p-nitrophenoxy)propane (EPN P), was crystallized. The structure of the inhibited complex was deter mined by X-ray crystallography to a resolution of 2.4 angstrom and ref ined to an R factor of 19%. The variant, SIV PR S4H, was shown to dimi nish the rate of autolysis by at least 4-fold without affecting enzyma tic parameters. The overall root mean square (rms) deviation of the a- carbons from the structure of HIV-1PR complexed with a peptidomimetic inhibitor (7HVP) was 1.16 angstrom. The major differences are concentr ated in three surface loops with rms differences between 1.2 and 2.1 a ngstrom. For 60% of the molecule the rms deviation was only 0.6 angstr om. The structure reveals one molecule of EPNP bound per protease dime r, a stoichiometry confirmed by mass spectral analysis. The epoxide mo iety forms a covalent bond with either of the active site aspartic aci ds of the dimer, and the phenyl moiety occupies the P1 binding site. T he EPNP nitro group interacts with Arg 8. This structure suggests a st arting template for the design of nonpeptide-based irreversible inhibi tors of the SIV and related HIV-1 and HIV-2 PRs.