STRUCTURAL-ANALYSIS OF INHIBITOR BINDING TO HIV-1 PROTEASE - IDENTIFICATION OF A COMMON BINDING MOTIF

Analysis of coordinates from ten crystal structures of HIV-I protease- inhibitor complexes (HIV-I-Pr) reveals that the energetically importan t contacts formed in these complexes involve a rather limited number o f atoms from only a few highly mutable residues. This common binding m otif relies primarily on hydrogen bonds to position each inhibitor bet ween the catalytic and the flap residues of HIV-1 protease, together w ith a set of hydrophobic interactions that flank the lengthwise edges of these inhibitors. Nine of thirteen known drug resistant HIV-1 prote ase mutations are located directly within this motif. These striking s imilarities in the details of inhibitor binding suggest that escape mu tants arising from treatment with any one of these HIV-1 protease inhi bitors will likely confer cross-resistance to other inhibitors utilizi ng the same binding pattern. It is suggested that the stability of the natural substrate, in contrast to the more rigid synthetic inhibitors , facilitates its adaptation to bind, for catalysis. (C) 1998 Elsevier Science B.V.