Cooperative effects of drug-resistance mutations in the flap region of HIV-1 protease
AuthorsFoulkes-Murzycki, Jennifer E.
Yilmaz, Nese Kurt
Shafer, Robert W.
Schiffer, Celia A.
UMass Chan AffiliationsDepartment of Biochemistry and Molecular Pharmacology
Document TypeJournal Article
MetadataShow full item record
AbstractUnderstanding 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.
SourceACS Chem Biol. 2013 Mar 15;8(3):513-8. doi: 10.1021/cb3006193. Epub 2012 Dec 27. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/29152
Related ResourcesLink to Article in PubMed