2ati
From Proteopedia
(New page: 200px<br /> <applet load="2ati" size="450" color="white" frame="true" align="right" spinBox="true" caption="2ati, resolution 1.9Å" /> '''Glycogen Phosphoryla...) |
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caption="2ati, resolution 1.9Å" /> | caption="2ati, resolution 1.9Å" /> | ||
'''Glycogen Phosphorylase Inhibitors'''<br /> | '''Glycogen Phosphorylase Inhibitors'''<br /> | ||
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==About this Structure== | ==About this Structure== | ||
| - | 2ATI is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with GLC, IHU and PLP as [http://en.wikipedia.org/wiki/ligands ligands]. 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:// | + | 2ATI is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=GLC:'>GLC</scene>, <scene name='pdbligand=IHU:'>IHU</scene> and <scene name='pdbligand=PLP:'>PLP</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. 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=2ATI OCA]. |
==Reference== | ==Reference== | ||
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[[Category: glycogen phosphorylase]] | [[Category: glycogen phosphorylase]] | ||
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Revision as of 15:14, 15 February 2008
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Glycogen Phosphorylase Inhibitors
Contents |
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.
Disease
Known disease associated with this structure: Glycogen storage disease VI OMIM:[232700]
About this Structure
2ATI is a Single protein structure of sequence from Homo sapiens with , and as ligands. Active as Phosphorylase, with EC number 2.4.1.1 Full crystallographic information is available from OCA.
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:16190745
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