University of Massachusetts Medical School Faculty Publications
Title
Cooperative effects of drug-resistance mutations in the flap region of HIV-1 protease
UMMS Affiliation
Department of Biochemistry and Molecular Pharmacology
Publication Date
2013-03-15
Document Type
Article
Subjects
HIV Protease; HIV-1; Drug Resistance, Viral
Disciplines
Biochemistry | Microbial Physiology | Virus Diseases
Abstract
Understanding the interdependence of multiple mutations in conferring drug resistance is crucial to the development of novel and robust inhibitors. As HIV-1 protease continues to adapt and evade inhibitors while still maintaining the ability to specifically recognize and efficiently cleave its substrates, the problem of drug resistance has become more complicated. Under the selective pressure of therapy, correlated mutations accumulate throughout the enzyme to compromise inhibitor binding, but characterizing their energetic interdependency is not straightforward. A particular drug resistant variant (L10I/G48V/I54V/V82A) displays extreme entropy-enthalpy compensation relative to wild-type enzyme but a similar variant (L10I/G48V/I54A/V82A) does not. Individual mutations of sites in the flaps (residues 48 and 54) of the enzyme reveal that the thermodynamic effects are not additive. Rather, the thermodynamic profile of the variants is interdependent on the cooperative effects exerted by a particular combination of mutations simultaneously present.
DOI of Published Version
10.1021/cb3006193
Source
ACS Chem Biol. 2013 Mar 15;8(3):513-8. doi: 10.1021/cb3006193. Epub 2012 Dec 27. Link to article on publisher's site
Related Resources
Journal/Book/Conference Title
ACS chemical biology
PubMed ID
23252515
Repository Citation
Foulkes-Murzycki JE, Rosi C, Yilmaz NK, Shafer RW, Schiffer CA. (2013). Cooperative effects of drug-resistance mutations in the flap region of HIV-1 protease. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.1021/cb3006193. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/138