3sym

Glycogen Phosphorylase b in complex with 3 -C-(hydroxymethyl)-beta-D-glucopyranonucleoside of 5-fluorouracil

spinqualitylabelsall models 3sym, resolution 2.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3sym is a 1 chain structure with sequence from Oryctolagus cuniculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.4Å Ligands: GP0, LLP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PYGM_RABIT Phosphorylase is an important allosteric enzyme in carbohydrate metabolism. Enzymes from different sources differ in their regulatory mechanisms and in their natural substrates. However, all known phosphorylases share catalytic and structural properties. Publication Abstract from PubMed Glycogen phosphorylase is a molecular target for the design of potential hypoglycaemic agents. Structure based design pinpointed that the 3'-position of glucopyranose equipped with a suitable group has the potential to form interactions with enzyme's cofactor, PLP, thus enhancing the inhibitory potency. Hence, we have investigated the binding of two ligands, 1-(beta-D-glucopyranosyl)5-fluorouracil (GlcFU) and its 3'-CH(2) OH glucopyranose derivative. Both ligands were found to be low muM inhibitors with K(i) values of 7.9 and 27.1 muM, respectively. X-ray crystallography revealed that the 3'-CH(2) OH glucopyranose substituent is indeed involved in additional molecular interactions with the PLP gamma-phosphate compared to GlcFU. However it is 3.4 times less potent. To elucidate this discovery, docking followed by post-docking Quantum Mechanics/Molecular Mechanics - Poisson Boltzmann Surface Area (QM/MM-PBSA) binding affinity calculations were performed. While the docking predictions failed to reflect the kinetic results, the QM/MM-PBSA revealed that the desolvation energy cost for binding of the 3'-CH(2) OH-substituted glucopyranose derivative out-weigh the enthalpy gains from the extra contacts formed. The benefits of performing post-docking calculations employing a more accurate solvation model and the QM/MM-PBSA methodology in lead optimization is therefore highlighted, specifically when the role of a highly polar/charged binding interface is significant. (c) 2012 John Wiley & Sons A/S. 3'-axial CH(2) OH substitution on glucopyranose does not increase glycogen phosphorylase inhibitory potency. QM/MM-PBSA calculations suggest why.,Manta S, Xipnitou A, Kiritsis C, Kantsadi AL, Hayes JM, Skamnaki VT, Lamprakis C, Kontou M, Zoumpoulakis P, Zographos SE, Leonidas DD, Komiotis D Chem Biol Drug Des. 2012 Feb 2. doi: 10.1111/j.1747-0285.2012.01349.x. PMID:22296957 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Glycogen phosphorylase 3D structures

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