2ati

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[[Image:2ati.gif|left|200px]]
[[Image:2ati.gif|left|200px]]
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{{Structure
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<!--
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|PDB= 2ati |SIZE=350|CAPTION= <scene name='initialview01'>2ati</scene>, resolution 1.9&Aring;
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The line below this paragraph, containing "STRUCTURE_2ati", creates the "Structure Box" on the page.
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|SITE=
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You may change the PDB parameter (which sets the PDB file loaded into the applet)
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|LIGAND= <scene name='pdbligand=GLC:GLUCOSE'>GLC</scene>, <scene name='pdbligand=IHU:N-(2-CHLORO-4-FLUOROBENZOYL)-N&#39;-(5-HYDROXY-2-METHOXYPHENYL)UREA'>IHU</scene>, <scene name='pdbligand=PLP:PYRIDOXAL-5&#39;-PHOSPHATE'>PLP</scene>
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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|ACTIVITY= <span class='plainlinks'>[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] </span>
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or leave the SCENE parameter empty for the default display.
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|GENE=
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-->
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|DOMAIN=
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{{STRUCTURE_2ati| PDB=2ati | SCENE= }}
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|RELATEDENTRY=[[1wut|1WUT]], [[1wuy|1WUY]], [[1wv0|1WV0]], [[1wv1|1WV1]]
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2ati FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ati OCA], [http://www.ebi.ac.uk/pdbsum/2ati PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2ati RCSB]</span>
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}}
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'''Glycogen Phosphorylase Inhibitors'''
'''Glycogen Phosphorylase Inhibitors'''
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[[Category: Schoenafinger, K.]]
[[Category: Schoenafinger, K.]]
[[Category: Wendt, K U.]]
[[Category: Wendt, K U.]]
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[[Category: glycogen phosphorylase]]
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[[Category: Glycogen phosphorylase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 19:27:26 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 01:57:04 2008''
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Revision as of 16:27, 3 May 2008

Image:2ati.gif

Template:STRUCTURE 2ati

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.

About this Structure

2ATI is a Single protein structure of sequence from Homo sapiens. 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 Page seeded by OCA on Sat May 3 19:27:26 2008

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