Impacts of drug resistance mutations on the structural asymmetry of the HIV-2 protease

• Main Authors: Pierre Laville, Sandrine Fartek, Natacha Cerisier, Delphine Flatters, Michel Petitjean, Leslie Regad
• Format: Article
• Language: English
• Published: BMC 2020-06-01
• Series: BMC Molecular and Cell Biology
• Subjects: HIV-2 protease; Drug-resistance mutations; Structural asymmetry; Structural alphabet
• Online Access: http://link.springer.com/article/10.1186/s12860-020-00290-1

Abstract Background Drug resistance is a severe problem in HIV treatment. HIV protease is a common target for the design of new drugs for treating HIV infection. Previous studies have shown that the crystallographic structures of the HIV-2 protease (PR2) in bound and unbound forms exhibit structural asymmetry that is important for ligand recognition and binding. Here, we investigated the effects of resistance mutations on the structural asymmetry of PR2. Due to the lack of structural data on PR2 mutants, the 3D structures of 30 PR2 mutants of interest have been modeled using an in silico protocol. Structural asymmetry analysis was carried out with an in-house structural-alphabet-based approach. Results The systematic comparison of the asymmetry of the wild-type structure and a large number of mutants highlighted crucial residues for PR2 structure and function. In addition, our results revealed structural changes induced by PR2 flexibility or resistance mutations. The analysis of the highlighted structural changes showed that some mutations alter protein stability or inhibitor binding. Conclusions This work consists of a structural analysis of the impact of a large number of PR2 resistant mutants based on modeled structures. It suggests three possible resistance mechanisms of PR2, in which structural changes induced by resistance mutations lead to modifications in the dimerization interface, ligand recognition or inhibitor binding.