2g9v
From Proteopedia
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'''The crystal structure of glycogen phosphorylase in complex with (3R,4R,5R)-5-hydroxymethylpiperidine-3,4-diol and phosphate''' | '''The crystal structure of glycogen phosphorylase in complex with (3R,4R,5R)-5-hydroxymethylpiperidine-3,4-diol and phosphate''' | ||
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[[Category: Tiraidis, C.]] | [[Category: Tiraidis, C.]] | ||
[[Category: Zographos, S E.]] | [[Category: Zographos, S E.]] | ||
| - | [[Category: | + | [[Category: Catalytic site]] |
| - | [[Category: | + | [[Category: Glycogen phosphorylase]] |
| - | [[Category: | + | [[Category: Rational inhibitor design]] |
| - | [[Category: | + | [[Category: Structure]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 04:51:55 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 01:51, 4 May 2008
The crystal structure of glycogen phosphorylase in complex with (3R,4R,5R)-5-hydroxymethylpiperidine-3,4-diol and phosphate
Overview
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 Structure
2G9V is a Single protein structure of sequence from Oryctolagus cuniculus. Full crystallographic information is available from OCA.
Reference
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 Page seeded by OCA on Sun May 4 04:51:55 2008
