Drug Resistance Mutation L76V Alters Nonpolar Interactions at the Flap-Core Interface of HIV-1 Protease
UMass Chan AffiliationsDepartment of Biochemistry and Molecular Pharmacology
RNA Therapeutics Institute
Document TypeJournal Article
KeywordsBiochemistry, Biophysics, and Structural Biology
Enzymes and Coenzymes
MetadataShow full item record
AbstractFour HIV-1 protease (PR) inhibitors, clinical inhibitors lopinavir and tipranavir, and two investigational compounds 4 and 5, were studied for their effect on the structure and activity of PR with drug-resistant mutation L76V (PRL76V). Compound 5 exhibited the best K i value of 1.9 nM for PRL76V, whereas the other three inhibitors had K i values of 4.5-7.6 nM, 2-3 orders of magnitude worse than for wild-type enzymes. Crystal structures showed only minor differences in interactions of inhibitors with PRL76V compared to wild-type complexes. The shorter side chain of Val76 in the mutant lost hydrophobic interactions with Lys45 and Ile47 in the flap, and with Asp30 and Thr74 in the protein core, consistent with decreased stability. Inhibitors forming additional polar interactions with the flaps or dimer interface of PRL76V were unable to compensate for the decrease in internal hydrophobic contacts. These structures provide insights for inhibitor design.
ACS Omega. 2018 Sep 30;3(9):12132-12140. doi: 10.1021/acsomega.8b01683. Epub 2018 Sep 27. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/48831
RightsCopyright © 2018 American Chemical Society. This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Except where otherwise noted, this item's license is described as Copyright © 2018 American Chemical Society. This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.