32] Modeling of structure of human immunodeficiency virus-1 protease with substrate based on crystal structure of rous sarcoma virus protease

Abstract

Publisher Summary This chapter presents the modeling of structure of human immunodeficiency virus-1(HIV-1) protease with substrate based on the crystal structure of Rous sarcoma virus (RSV) protease. Human immunodeficiency virus, in common with other retroviruses, encodes a protease, which is required for processing of the gag and pol protein precursors and is essential for the production of infectious virus particles. Other retroviral proteases show similarities in amino acid sequence with the HIV retroviral protease (PR) and some cross-specificity for peptide cleavage sites, which suggests that three-dimensional structures will be conserved. All known retroviral proteases contain the conserved catalytic triplet, Asp-Thr/Ser-Gly, which is characteristic of the aspartic protease family, and the enzymes are inhibited by typical aspartic protease inhibitors. Therefore, a model of the structure of the HIV-1 protease complexed with substrate was built with the aim of designing active-site inhibitors. At the same time, the structure of recombinant HIV-1 PR was determined, and, later, the structure of chemically synthesized HIV-1 PR was determined and refined to an R factor of 18.4% at 2.8 A resolution. In a study described in the chapter, the crystal structure of HIV-I PR complexed with inhibitor was determined. This has made it possible to compare the predicted model structure of HIV-1 PR with the crystal structure.