Download MendeleyNon-active site mutations in the HIV protease: Diminished drug binding affinity is achieved through modulating the hydrophobic sliding mechanism.
Sherry, D., Pandian, R., Sayed, Y.(2022) Int J Biol Macromol 217: 27-41
- PubMed: 35817239
- DOI: https://doi.org/10.1016/j.ijbiomac.2022.07.033
- Primary Citation of Related Structures:
6I45 - PubMed Abstract:
The global HIV/AIDS epidemic still currently affects approximately 38 million individuals globally. The protease enzyme of the human immunodeficiency virus is a major drug target in antiviral therapy, however, under the influence of reverse transcriptase and in the context of drug pressure, the rapid PR mutation rate contributes significantly to clinical failure. The set of cooperative non-active site mutations, I13V/I62V/V77I, have been associated with reduced inhibitor susceptibility and are the focus of the current study. When compared to the wild-type protease the mutant protease exhibited decreased binding affinities towards ATV and DRV by 64- and 12-fold, respectively, and decreased the overall favourable Gibbs free energy for ATV, DRV, RTV and SQV. Moreover, these mutations decreased the thermal stability of the protease when in complex with ATV and DRV by approximately 6.4 and 4.2 °C, respectively. The crystal structure of the mutant protease revealed that the location of these mutations and their effect on the hydrophobic sliding mechanism may be crucial in their role in resistance.
Organizational Affiliation:
Protein Structure-Function Research Unit, School of Molecular and Cell Biology, University of the Witwatersrand, Johannesburg 2050, South Africa.
