2g9r
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The crystal structure of glycogen phosphorylase b in complex with (3R,4R,5R)-5-hydroxymethyl-1-(3-phenylpropyl)-piperidine-3,4-diol
OverviewOverview
Iminosugars DAB (5), isofagomine (9), and several N-substituted, derivatives have been identified as potent inhibitors of liver glycogen, phosphorylase a (IC(50) = 0.4-1.2 microM) and of basal and, glucagon-stimulated glycogenolysis (IC(50) = 1-3 microM). The X-ray, structures of 5, 9, and its N-3-phenylpropyl analogue 8 in complex with, rabbit muscle glycogen phosphorylase (GPb) shows that iminosugars bind, tightly at the catalytic site in the presence of the substrate phosphate, and induce conformational changes that characterize the R-state, conformation of the enzyme. Charged nitrogen N1 is within hydrogen-bonding, distance with the carbonyl oxygen of His377 (5) and in ionic contact with, the substrate phosphate oxygen (8 and 9). Our findings suggest that the, inhibitors function as oxocarbenium ion transition-state analogues. The, conformational change to the R state provides an explanation for previous, findings that 5, unlike inhibitors that favor the T state, promotes, phosphorylation of GPb in hepatocytes with sequential inactivation of, glycogen synthase.
About this StructureAbout this Structure
2G9R is a Single protein structure of sequence from Oryctolagus cuniculus with G27 as ligand. Active as Phosphorylase, with EC number 2.4.1.1 Full crystallographic information is available from OCA.
ReferenceReference
Iminosugars as potential inhibitors of glycogenolysis: structural insights into the molecular basis of glycogen phosphorylase inhibition., Oikonomakos NG, Tiraidis C, Leonidas DD, Zographos SE, Kristiansen M, Jessen CU, Norskov-Lauritsen L, Agius L, J Med Chem. 2006 Sep 21;49(19):5687-701. PMID:16970395
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