Structural analysis of inhibitor binding to HIV-1 protease: identification of a common binding motif

Abstract

Analysis of coordinates from ten crystal structures of HIV-1 protease–inhibitor complexes (HIV-1–Pr) reveals that the energetically important contacts formed in these complexes involve a rather limited number of atoms from only a few highly mutable residues. This common binding motif relies primarily on hydrogen bonds to position each inhibitor between the catalytic and the flap residues of HIV-1 protease, together with a set of hydrophobic interactions that flank the lengthwise edges of these inhibitors. Nine of thirteen known drug resistant HIV-1 protease mutations are located directly within this motif. These striking similarities in the details of inhibitor binding suggest that escape mutants arising from treatment with any one of these HIV-1 protease inhibitors will likely confer cross-resistance to other inhibitors utilizing 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.