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dc.contributor.authorFoulkes-Murzycki, Jennifer E.
dc.contributor.authorRosi, Christina
dc.contributor.authorYilmaz, Nese Kurt
dc.contributor.authorShafer, Robert W.
dc.contributor.authorSchiffer, Celia A.
dc.date2022-08-11T08:08:22.000
dc.date.accessioned2022-08-23T15:52:30Z
dc.date.available2022-08-23T15:52:30Z
dc.date.issued2013-03-15
dc.date.submitted2013-07-08
dc.identifier.citationACS Chem Biol. 2013 Mar 15;8(3):513-8. doi: 10.1021/cb3006193. Epub 2012 Dec 27. <a href="http://dx.doi.org/10.1021/cb3006193" target="_blank">Link to article on publisher's site</a>
dc.identifier.issn1554-8929 (Linking)
dc.identifier.doi10.1021/cb3006193
dc.identifier.pmid23252515
dc.identifier.urihttp://hdl.handle.net/20.500.14038/29152
dc.description.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.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=23252515&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://dx.doi.org/10.1021/cb3006193
dc.subjectHIV Protease
dc.subjectHIV-1
dc.subjectDrug Resistance, Viral
dc.subjectBiochemistry
dc.subjectMicrobial Physiology
dc.subjectVirus Diseases
dc.titleCooperative effects of drug-resistance mutations in the flap region of HIV-1 protease
dc.typeJournal Article
dc.source.journaltitleACS chemical biology
dc.source.volume8
dc.source.issue3
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/faculty_pubs/138
dc.identifier.contextkey4295157
html.description.abstract<p>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.</p>
dc.identifier.submissionpathfaculty_pubs/138
dc.contributor.departmentDepartment of Biochemistry and Molecular Pharmacology
dc.source.pages513-8


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