STRUCTURE OF A G48H MUTANT OF HIV-1 PROTEASE EXPLAINS HOW GLYCINE-48 REPLACEMENTS PRODUCE MUTANTS RESISTANT TO INHIBITOR DRUGS

The crystal structure of human immunodeficiency virus type 1 (HIV-1) p rotease mutant G48H with peptidic inhibitor U-89360E is described. Com parison with wild-type protease-inhibitor complex shows that mutation of flap residue 48 to histidine allows stabilizing van der Waals conta cts between the side chains of His(48) and Phe(53) as well as between His(48) and the P-2' and P-3' inhibitor subsites, The flap region is l ess mobile than in the wild-type enzyme. A model of saquinavir-resista nt mutant protease G48V in complex with saquinavir predicts interactio ns similar to those found in the G48H crystal. Energetic calculations confirm the similarity of the His and Val(48) interactions. (C) 1997 F ederation of European Biochemical Societies.