2ati: Difference between revisions

Revision as of 07:20, 28 July 2008

This article has been automatically seeded. Changes to this page should pertain to the PDB entry only and not to the protein or biomolecule in general.

File:2ati.png

Template:STRUCTURE 2ati

Glycogen Phosphorylase InhibitorsGlycogen Phosphorylase Inhibitors

Template:ABSTRACT PUBMED 16190745

About this StructureAbout this Structure

2ATI is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

ReferenceReference

Acyl ureas as human liver glycogen phosphorylase inhibitors for the treatment of type 2 diabetes., Klabunde T, Wendt KU, Kadereit D, Brachvogel V, Burger HJ, Herling AW, Oikonomakos NG, Kosmopoulou MN, Schmoll D, Sarubbi E, von Roedern E, Schonafinger K, Defossa E, J Med Chem. 2005 Oct 6;48(20):6178-93. PMID:16190745

Crystallographic studies on acyl ureas, a new class of glycogen phosphorylase inhibitors, as potential antidiabetic drugs., Oikonomakos NG, Kosmopoulou MN, Chrysina ED, Leonidas DD, Kostas ID, Wendt KU, Klabunde T, Defossa E, Protein Sci. 2005 Jul;14(7):1760-71. PMID:15987904

Activation of human liver glycogen phosphorylase by alteration of the secondary structure and packing of the catalytic core., Rath VL, Ammirati M, LeMotte PK, Fennell KF, Mansour MN, Danley DE, Hynes TR, Schulte GK, Wasilko DJ, Pandit J, Mol Cell. 2000 Jul;6(1):139-48. PMID:10949035

Page seeded by OCA on Mon Jul 28 07:20:29 2008

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OCA

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 {{STRUCTURE_2ati|  PDB=2ati  |  SCENE=  }}
-'''Glycogen Phosphorylase Inhibitors'''
+===Glycogen Phosphorylase Inhibitors===
-==Overview==
+<!--
-Using a focused screening approach, acyl ureas have been discovered as a new class of inhibitors of human liver glycogen phosphorylase (hlGPa). The X-ray structure of screening hit 1 (IC50 = 2 microM) in a complex with rabbit muscle glycogen phosphorylase b reveals that 1 binds at the AMP site, the main allosteric effector site of the dimeric enzyme. A first cycle of chemical optimization supported by X-ray structural data yielded derivative 21, which inhibited hlGPa with an IC50 of 23 +/- 1 nM, but showed only moderate cellular activity in isolated rat hepatocytes (IC50 = 6.2 microM). Further optimization was guided by (i) a 3D pharmacophore model that was derived from a training set of 24 compounds and revealed the key chemical features for the biological activity and (ii) the 1.9 angstroms crystal structure of 21 in complex with hlGPa. A second set of compounds was synthesized and led to 42 with improved cellular activity (hlGPa IC50 = 53 +/- 1 nM; hepatocyte IC50 = 380 nM). Administration of 42 to anaesthetized Wistar rats caused a significant reduction of the glucagon-induced hyperglycemic peak. These findings are consistent with the inhibition of hepatic glycogenolysis and support the use of acyl ureas for the treatment of type 2 diabetes.
+The line below this paragraph, {{ABSTRACT_PUBMED_16190745}}, adds the Publication Abstract to the page
+(as it appears on PubMed at http://www.pubmed.gov), where 16190745 is the PubMed ID number.
+-->
+{{ABSTRACT_PUBMED_16190745}}
 ==About this Structure==
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 ==Reference==
 Acyl ureas as human liver glycogen phosphorylase inhibitors for the treatment of type 2 diabetes., Klabunde T, Wendt KU, Kadereit D, Brachvogel V, Burger HJ, Herling AW, Oikonomakos NG, Kosmopoulou MN, Schmoll D, Sarubbi E, von Roedern E, Schonafinger K, Defossa E, J Med Chem. 2005 Oct 6;48(20):6178-93. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16190745 16190745]
+Crystallographic studies on acyl ureas, a new class of glycogen phosphorylase inhibitors, as potential antidiabetic drugs., Oikonomakos NG, Kosmopoulou MN, Chrysina ED, Leonidas DD, Kostas ID, Wendt KU, Klabunde T, Defossa E, Protein Sci. 2005 Jul;14(7):1760-71. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15987904 15987904]
+Activation of human liver glycogen phosphorylase by alteration of the secondary structure and packing of the catalytic core., Rath VL, Ammirati M, LeMotte PK, Fennell KF, Mansour MN, Danley DE, Hynes TR, Schulte GK, Wasilko DJ, Pandit J, Mol Cell. 2000 Jul;6(1):139-48. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/10949035 10949035]
 [[Category: Homo sapiens]]
 [[Category: Phosphorylase]]
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 [[Category: Wendt, K U.]]
 [[Category: Glycogen phosphorylase]]
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