Amprenavir complexes with HIV-1 protease and its drug-resistant mutants altering hydrophobic clusters.

ABSTRACT: The structural and kinetic effects of amprenavir (APV), a clinical HIV protease (PR) inhibitor, were analyzed with wild-type enzyme and mutants with single substitutions of V32I, I50V, I54V, I54M, I84V and L90M that are common in drug resistance. Crystal structures of the APV complexes at resolutions of 1.02-1.85 Å reveal the structural changes due to the mutations. Substitution of the larger side chains in PR(V32I) , PR(I54M) and PR(L90M) resulted in the formation of new hydrophobic contacts with flap residues, residues 79 and 80, and Asp25, respectively. Mutation to smaller side chains eliminated hydrophobic interactions in the PR(I50V) and PR(I54V) structures. The PR(I84V)-APV complex had lost hydrophobic contacts with APV, the PR(V32I)-APV complex showed increased hydrophobic contacts

SUBMITTER: Shen CH 

PROVIDER: S-EPMC2975871 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature