An alternate binding site for the P1-P3 group of a class of potent HIV-1 protease inhibitors as a result of concerted structural change in the 80s loop of the protease

Structures of the complexes of HIV protease inhibitor L-756,423 with the HI V-1 wild-type protease and of the inhibitors Indinavir, L-739,622 and Saqui navir with the mutant protease (9X) containing nine point mutations (Leu10V al, Lys20Met, Leu24Ile, Ser37Asp, Met46Ile, Ile54Val, Leu63Pro, Ala71Val, V al82Thr) have been determined. Comparative analysis of these structures rev eals an alternate binding pocket for the P1-P3 group of Indinavir and L-756 ,423. The alternate binding pocket is a result of concerted structural chan ge in the 80s loop (residues 79-82) of the protease. The 80s loop is pulled away from the active site in order to accommodate the P1-P3 group, which i s sandwiched between the flap and the 80s loop. This structural change is o bserved for the complexes of the wild type as well as the 9X mutant proteas e. The study reveals that the 80s loop is an intrinsically flexible loop in the wild-type HIV-1 protease and that mutations in this loop are not neces sary to result in conformational changes. Conformation of this loop in the complex depends primarily upon the nature of the bound inhibitor and may be influenced by mutations in the protease. The results underscore the need t o understand the intrinsic structural plasticity of the protease for the de sign of effective inhibitors against the wild-type and drug-resistant enzym e forms. In addition, the alternate binding pocket for the P1-P3 group of I ndinavir and L-756,423 may be exploited for the design of potent inhibitors .