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Thermodynamic and structural analysis of HIV protease resistance to darunavir - analysis of heavily mutated patient- derived HIV-1 proteases
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SYSNO ASEP 0427922 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Thermodynamic and structural analysis of HIV protease resistance to darunavir - analysis of heavily mutated patient- derived HIV-1 proteases Author(s) Kožíšek, Milan (UOCHB-X) RID, ORCID
Lepšík, Martin (UOCHB-X) RID, ORCID
Grantz Šašková, Klára (UOCHB-X) RID, ORCID
Brynda, Jiří (UMG-J) RID
Konvalinka, Jan (UOCHB-X) RID, ORCID
Řezáčová, Pavlína (UOCHB-X) RID, ORCIDNumber of authors 6 Source Title FEBS Journal - ISSN 1742-464X
Roč. 281, č. 7 (2014), s. 1834-1847Number of pages 14 s. Language eng - English Country GB - United Kingdom Keywords enthropic contribution ; HIV protease inhibitors ; isothermal titration calorimetry ; resistance mutation ; X-ray crystallography Subject RIV CE - Biochemistry R&D Projects GAP207/11/1798 GA ČR - Czech Science Foundation (CSF) Institutional support UOCHB-X - RVO:61388963 ; UMG-J - RVO:68378050 UT WOS 000333676000010 EID SCOPUS 84897562966 DOI 10.1111/febs.12743 Annotation We report enzymologic, thermodynamic and structural analyses of a series of six clinically derived mutant HIV proteases (PR) resistant to darunavir. As many as 20 mutations in the resistant PRs decreased the binding affinity of darunavir by up to 13000-fold, mostly because of a less favorable enthalpy of binding that was only partially compensated by the entropic contribution. X-ray structure analysis suggested that the drop in enthalpy of darunavir binding to resistantPR species was mostly the result of a decrease in the number of hydrogen bonds and a loosening of the fit between the inhibitor and the mutated enzymes. The favorable entropic contribution to darunavir binding to mutated PR variants correlated with a larger burial of the nonpolar solvent-accessible surface area upon inhibitor binding. We show that even very dramatic changes in the PR sequence leading to the loss of hydrogen bonds with the inhibitor could be partially compensated by the entropy contribution as a result of the burial of the larger nonpolar surface area of the mutated HIV PRs. Workplace Institute of Organic Chemistry and Biochemistry Contact asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418 Year of Publishing 2015
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