3-DIMENSIONAL STRUCTURE OF A SIMIAN IMMUNODEFICIENCY VIRUS PROTEASE INHIBITOR COMPLEX - IMPLICATIONS FOR THE DESIGN OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 AND TYPE-2 PROTEASE INHIBITORS

Simian immunodeficiency virus (SIV) proteins have considerable amino a cid sequence homology to those from human immunodeficiency virus (HIV) ; thus monkeys are considered useful models for the preclinical evalua tion of acquired immune deficiency syndrome (AIDS) therapeutics. We ha ve crystallized and determined the three-dimensional structure of SIV protease bound to the hydroxyethylene isostere inhibitor SKF107457. Cr ystals of the complex were grown from 25-32% saturated sodium chloride , by the hanging drop method of vapor diffusion. They belong to the or thorhombic space group I222, with a = 46.3 angstrom, b = 101.5 angstro m, and c = 118.8 angstrom. The structure has been determined at 2.5-an gstrom resolution by molecular replacement and refined to a crystallog raphic discrepancy factor, R (=SIGMA\\F(o)\ - \F(c)\\/SIGMA\F(o)\), of 0.189. The overall structure of the complex is very similar to previo usly reported structures of HIV-1 protease bound to inhibitors. The in hibitor is bound in a conformation that is almost identical to that fo und for the same inhibitor bound to HIV-1 protease, except for an over all translation of the inhibitor, varying along the backbone atoms fro m about 1.0 angstrom at the termini to about 0.5 angstrom around the s cissile bond surrogate. The structures of the SIV and HIV-1 proteins v ary significantly only in three surface loops composed of amino acids 15-20, 34-45, and 65-70. Superposition of the 1188 protein backbone at oms from the two structures gives an rms deviation of 1.0 angstrom; th is number is reduced to 0.6 angstrom when atoms from the three surface loops are eliminated from the rms calculation. Given the considerable amino acid sequence homology of SIV and HIV-2 proteases, we predict t hat their three-dimensional structures will be practically identical. Comparison of the structures of the SIV and HIV-1 protease/SKF107457 c omplexes suggests that to design inhibitors that are equally effective against HIV-1 and -2, one must maintain a balance in the size of the side chains at P2, P1, P1', and P2'. In other words, large side chains at one side of the inhibitor (P1 and P2') require small ones at the o pposite side (P2 and P1'). Also, the high similarity in the active-sit e geometry of the proteases from SIV and HIV confirms the notion that monkeys are useful models for the preclinical evaluation of acquired i mmune deficiency syndrome (AIDS) therapeutics.