1WV1
Crystallographic studies on acyl ureas, a new class of inhibitors of glycogenphosphorylase. Broad specificity of the allosteric site
Summary for 1WV1
Entry DOI | 10.2210/pdb1wv1/pdb |
Related | 1WUT 1WUY 1WV0 3AMV |
Descriptor | Glycogen phosphorylase, muscle form, PYRIDOXAL-5'-PHOSPHATE, 5-[3-({[(2,4-DICHLOROBENZOYL)AMINO]CARBONYL}AMINO)-2-METHYLPHENOXY]PENTANOIC ACID, ... (4 entities in total) |
Functional Keywords | glycogenolysis, type 2 diabetes, transferase |
Biological source | Oryctolagus cuniculus (rabbit) |
Total number of polymer chains | 1 |
Total formula weight | 97977.63 |
Authors | Oikonomakos, N.G.,Kosmopoulou, M.N.,Chrysina, E.D.,Leonidas, D.D.,Klabunde, T.,Wendt, K.U.,Defossa, E. (deposition date: 2004-12-10, release date: 2005-12-10, Last modification date: 2011-07-13) |
Primary citation | Oikonomakos, N.G.,Kosmopoulou, M.N.,Chrysina, E.D.,Leonidas, D.D.,Kostas, I.D.,Wendt, K.U.,Klabunde, T.,Defossa, E. Crystallographic studies on acyl ureas, a new class of glycogen phosphorylase inhibitors, as potential antidiabetic drugs Protein Sci., 14:1760-1771, 2005 Cited by PubMed Abstract: Acyl ureas were discovered as a novel class of inhibitors for glycogen phosphorylase, a molecular target to control hyperglycemia in type 2 diabetics. This series is exemplified by 6-{2,6-Dichloro- 4-[3-(2-chloro-benzoyl)-ureido]-phenoxy}-hexanoic acid, which inhibits human liver glycogen phosphorylase a with an IC(50) of 2.0 microM. Here we analyze four crystal structures of acyl urea derivatives in complex with rabbit muscle glycogen phosphorylase b to elucidate the mechanism of inhibition of these inhibitors. The structures were determined and refined to 2.26 Angstroms resolution and demonstrate that the inhibitors bind at the allosteric activator site, where the physiological activator AMP binds. Acyl ureas induce conformational changes in the vicinity of the allosteric site. Our findings suggest that acyl ureas inhibit glycogen phosphorylase by direct inhibition of AMP binding and by indirect inhibition of substrate binding through stabilization of the T' state. PubMed: 15987904DOI: 10.1110/ps.051432405 PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (2.26 Å) |
Structure validation
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