Cooperative effects of drug-resistance mutations in the flap region of HIV-1 protease
Authors
Foulkes-Murzycki, Jennifer E.Rosi, Christina
Yilmaz, Nese Kurt
Shafer, Robert W.
Schiffer, Celia A.
UMass Chan Affiliations
Department of Biochemistry and Molecular PharmacologyDocument Type
Journal ArticlePublication Date
2013-03-15
Metadata
Show full item recordAbstract
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.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 siteDOI
10.1021/cb3006193Permanent Link to this Item
http://hdl.handle.net/20.500.14038/29152PubMed ID
23252515Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1021/cb3006193