Εξειδίκευση τύπου :	Άρθρο σε επιστημονικό περιοδικό
Τίτλος:	Sourcing the affinity of flavonoids for the glycogen phosphorylase inhibitor site via crystallography, kinetics and QM/MM-PBSA binding studies: Comparison of chrysin and flavopiridol
Δημιουργός/Συγγραφέας:	Tsitsanou K.E. Hayes J.M. Keramioti M. Mamais M. [EL] Οικονομάκος, Νίκος Γ.[EN] Oikonomakos, Nikos G. Kato A. [EL] Λεωνίδας, Δημήτρης Δ.[EN] Leonidas, Demetres D. [EL] Ζωγράφος, Σπύρος Ε.[EN] Zographos, Spyros E.
Ημερομηνία:	2013
Γλώσσα:	Αγγλικά
ISSN:	0278-6915
DOI:	10.1016/j.fct.2012.12.030
Άλλο:	PubMed ID: 23279842
Περίληψη:	Flavonoids have been discovered as novel inhibitors of glycogen phosphorylase (GP), a target to control hyperglycemia in type 2 diabetes. To elucidate the mechanism of inhibition, we have determined the crystal structure of the GPb-chrysin complex at 1.9Å resolution. Chrysin is accommodated at the inhibitor site intercalating between the aromatic side chains of Phe285 and Tyr613 through π-stacking interactions. Chrysin binds to GPb ~15 times weaker (Ki=19.01μM) than flavopiridol (Ki=1.24μM), exclusively at the inhibitor site, and both inhibitors display similar behavior with respect to AMP. To identify the source of flavopiridols' stronger affinity, molecular docking with Glide and postdocking binding free energy calculations using QM/MM-PBSA have been performed and compared. Whereas docking failed to correctly rank inhibitor binding conformations, the QM/MM-PBSA method employing M06-2X/6-31+G* to model the π-stacking interactions correctly reproduced the experimental results. Flavopiridols' greater binding affinity is sourced to favorable interactions of the cationic 4-hydroxypiperidin-1-yl substituent with GPb, with desolvation effects limited by the substituent conformation adopted in the crystallographic complex. Further successful predictions using QM/MM-PBSA for the flavonoid quercetagetin (which binds at the allosteric site) leads us to propose the methodology as a useful and inexpensive tool to predict flavonoid binding.
Τίτλος πηγής δημοσίευσης:	Food and Chemical Toxicology
Τόμος/Κεφάλαιο:	61
Σελίδες:	14-27
Θεματική Κατηγορία:	[EL] Βιολογία (Γενικά)[EN] Biology (General) [EL] Χημεία (Γενικά)[EN] Chemistry (General)
Λέξεις-Κλειδιά:	Chrysin Flavonoids Flavopiridol Glycogen phosphorylase Quercetagetin Type 2 diabetes
Αξιολόγηση από ομότιμους (peer reviewed):	Ναι
Κάτοχος πνευματικών δικαιωμάτων:	© 2012 Elsevier Ltd.
Σημειώσεις:	GA-230146; MEST-CT-020575, MTKD-CT-2006-042776; Seventh Framework Programme, FP7: 245866; European Commission, EC; General Secretariat for Research and Technology, GSRT; Sixth Framework Programme, FP6; Ministerio de Fomento. This work was financially supported by an EU Marie Curie Early Stage Training (EST) Contract No MEST-CT-020575; a Marie Curie Host Fellowships for the Transfer of Knowledge (ToK) Contract No MTKD-CT-2006-042776; «Excellence in Research Institutes» Greek General Secretariat for Research and Technology (2nd cycle), Ministry of Development; the EU FP7-REGPOT-2008-1 Project ‘‘EUROSTRUCT’’ (GA-230146) and the EU FP7-REGPOT-2009-1 Project ‘‘ARCADE’’ (GA-245866). Work at the Synchrotron Radiation Sources, CCLRC, Daresbury, England, MAX-lab, Lund, Sweden and EMBL Hamburg Outstation, Germany, was supported by funding provided by the European Commission under the FP6 and FP7 Research Infrastructure Actions “Structuring the European Research Area” and ‘‘ELISA’’ (European Light Sources Activities). This work was also supported in part by the Postgraduate Programmes ‘‘Biotechnology-Quality assessment in Nutrition and the Environment”, ‘‘Application of Molecular Biology-Molecular Genetics-Molecular Markers”, Department of Biochemistry and Biotechnology, University of Thessaly.
Εμφανίζεται στις συλλογές:	Ινστιτούτο Χημικής Βιολογίας - Επιστημονικό έργο