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| [[Image:2g9u.jpg|left|200px]] | | {{Seed}} |
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| {{STRUCTURE_2g9u| PDB=2g9u | SCENE= }} | | {{STRUCTURE_2g9u| PDB=2g9u | SCENE= }} |
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| '''The crystal structure of glycogen phosphorylase in complex with (3R,4R,5R)-5-hydroxymethyl-1-(3-phenylpropyl)-piperidine-3,4-diol and phosphate'''
| | ===The crystal structure of glycogen phosphorylase in complex with (3R,4R,5R)-5-hydroxymethyl-1-(3-phenylpropyl)-piperidine-3,4-diol and phosphate=== |
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| ==Overview==
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| 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.
| | The line below this paragraph, {{ABSTRACT_PUBMED_16970395}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 16970395 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_16970395}} |
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| ==About this Structure== | | ==About this Structure== |
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| [[Category: Rational inhibitor design]] | | [[Category: Rational inhibitor design]] |
| [[Category: Structure]] | | [[Category: Structure]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 04:51:52 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 01:09:01 2008'' |