2g9r: Difference between revisions
New page: left|200px<br /><applet load="2g9r" size="450" color="white" frame="true" align="right" spinBox="true" caption="2g9r, resolution 2.07Å" /> '''The crystal structur... |
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[[Image:2g9r.jpg|left|200px]]<br /><applet load="2g9r" size=" | [[Image:2g9r.jpg|left|200px]]<br /><applet load="2g9r" size="350" color="white" frame="true" align="right" spinBox="true" | ||
caption="2g9r, resolution 2.07Å" /> | caption="2g9r, resolution 2.07Å" /> | ||
'''The crystal structure of glycogen phosphorylase b in complex with (3R,4R,5R)-5-hydroxymethyl-1-(3-phenylpropyl)-piperidine-3,4-diol'''<br /> | '''The crystal structure of glycogen phosphorylase b in complex with (3R,4R,5R)-5-hydroxymethyl-1-(3-phenylpropyl)-piperidine-3,4-diol'''<br /> | ||
==Overview== | ==Overview== | ||
Iminosugars DAB (5), isofagomine (9), and several N-substituted | 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== | ==About this Structure== | ||
2G9R is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Oryctolagus_cuniculus Oryctolagus cuniculus] with G27 as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Phosphorylase Phosphorylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.1.1 2.4.1.1] Full crystallographic information is available from [http:// | 2G9R is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Oryctolagus_cuniculus Oryctolagus cuniculus] with <scene name='pdbligand=G27:'>G27</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Phosphorylase Phosphorylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.1.1 2.4.1.1] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2G9R OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Phosphorylase]] | [[Category: Phosphorylase]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Leonidas, D | [[Category: Leonidas, D D.]] | ||
[[Category: Oikonomakos, N | [[Category: Oikonomakos, N G.]] | ||
[[Category: Tiraidis, C.]] | [[Category: Tiraidis, C.]] | ||
[[Category: Zographos, S | [[Category: Zographos, S E.]] | ||
[[Category: G27]] | [[Category: G27]] | ||
[[Category: catalytic site]] | [[Category: catalytic site]] | ||
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[[Category: structure]] | [[Category: structure]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:29:34 2008'' | ||
Revision as of 18:29, 21 February 2008
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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 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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