Počet záznamů: 1

Thermodynamic and structural analysis of HIV protease resistance to darunavir - analysis of heavily mutated patient- derived HIV-1 proteases

SYSNO ASEP	0427922
Druh ASEP	J - Článek v odborném periodiku
Zařazení RIV	J - Článek v odborném periodiku
Poddruh J	Článek ve WOS
Název	Thermodynamic and structural analysis of HIV protease resistance to darunavir - analysis of heavily mutated patient- derived HIV-1 proteases
Tvůrce(i)	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, ORCID}
Celkový počet autorů	6
Zdroj.dok.	FEBS Journal - ISSN 1742-464X Roč. 281, č. 7 (2014), s. 1834-1847
Poč.str.	14 s.
Jazyk dok.	eng - angličtina
Země vyd.	GB - Velká Británie
Klíč. slova	enthropic contribution ; HIV protease inhibitors ; isothermal titration calorimetry ; resistance mutation ; X-ray crystallography
Vědní obor RIV	CE - Biochemie
CEP	GAP207/11/1798 GA ČR - Grantová agentura ČR
Institucionální podpora	UOCHB-X - RVO:61388963 ; UMG-J - RVO:68378050
UT WOS	000333676000010
EID SCOPUS	84897562966
DOI	10.1111/febs.12743
Anotace	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.
Pracoviště	Ústav organické chemie a biochemie
Kontakt	asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Viktorie Chládková, Tel.: 232 002 434
Rok sběru	2015

Počet záznamů: 1