3EBO

Glycogen Phosphorylase b/Chrysin complex

Summary for 3EBO

• Entry DOI: 10.2210/pdb3ebo/pdb
• Related: 1c8k 1e1y 3EBP
• Descriptor: Glycogen phosphorylase, muscle form, chrysin (3 entities in total)
• Functional Keywords: glycogen phosphorylase, catalytic site, rational inhibitor design, glycogenolysis, diabetes type 2, allosteric enzyme, carbohydrate metabolism, glycogen metabolism, glycosyltransferase, nucleotide-binding, phosphoprotein, pyridoxal phosphate, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Oryctolagus cuniculus (European rabbit,Japanese white rabbit,domestic rabbit,rabbits)
• Total number of polymer chains: 1
• Total formula weight: 97773.56

Authors

Oikonomakos, N.G.,Zographos, S.E.,Leonidas, D.D.,Hayes, J.M.,Tiraidis, C.,Alexacou, K.-M. (deposition date: 2008-08-28, release date: 2009-09-01, Last modification date: 2023-11-15)

Primary citation

Tsitsanou, K.E.,Hayes, J.M.,Keramioti, M.,Mamais, M.,Oikonomakos, N.G.,Kato, A.,Leonidas, D.D.,Zographos, S.E.
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
Food Chem.Toxicol., 61:14-27, 2013

PubMed Abstract: 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 1.9 Å 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 approximately 15 times weaker (Ki=19.01 μM) than flavopiridol (Ki=1.24 μM), 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.

PubMed: 23279842
DOI: 10.1016/j.fct.2012.12.030

Experimental method

X-RAY DIFFRACTION (1.9 Å)