2off

The crystal structure of Glycogen Phosphorylase b in complex with a potent allosteric inhibitor

spinqualitylabelsall models 2off, resolution 2.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2off 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 2.2Å Ligands: LLP, OFF 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. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed FR258900 has been discovered as a novel inhibitor of human liver glycogen phosphorylase a and proved to suppress hepatic glycogen breakdown and reduce plasma glucose concentrations in diabetic mice models. To elucidate the mechanism of inhibition, we have determined the crystal structure of the cocrystallized rabbit muscle glycogen phosphorylase b-FR258900 complex and refined it to 2.2 A resolution. The structure demonstrates that the inhibitor binds at the allosteric activator site, where the physiological activator AMP binds. The contacts from FR258900 to glycogen phosphorylase are dominated by nonpolar van der Waals interactions with Gln71, Gln72, Phe196, and Val45' (from the symmetry-related subunit), and also by ionic interactions from the carboxylate groups to the three arginine residues (Arg242, Arg309, and Arg310) that form the allosteric phosphate-recognition subsite. The binding of FR258900 to the protein promotes conformational changes that stabilize an inactive T-state quaternary conformation of the enzyme. The ligand-binding mode is different from those of the potent phenoxy-phthalate and acyl urea inhibitors, previously described, illustrating the broad specificity of the allosteric site. FR258900, a potential anti-hyperglycemic drug, binds at the allosteric site of glycogen phosphorylase.,Tiraidis C, Alexacou KM, Zographos SE, Leonidas DD, Gimisis T, Oikonomakos NG Protein Sci. 2007 Aug;16(8):1773-82. Epub 2007 Jun 28. PMID:17600143 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Glycogen phosphorylase 3D structures

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