1wut
From Proteopedia
(New page: 200px<br /><applet load="1wut" size="450" color="white" frame="true" align="right" spinBox="true" caption="1wut, resolution 2.26Å" /> '''Acyl Ureas as Human ...) |
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| - | [[Image:1wut.gif|left|200px]]<br /><applet load="1wut" size=" | + | [[Image:1wut.gif|left|200px]]<br /><applet load="1wut" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1wut, resolution 2.26Å" /> | caption="1wut, resolution 2.26Å" /> | ||
'''Acyl Ureas as Human Liver Glycogen Phosphorylase Inhibitors for the Treatment of Type 2 Diabetes'''<br /> | '''Acyl Ureas as Human Liver Glycogen Phosphorylase Inhibitors for the Treatment of Type 2 Diabetes'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Acyl ureas were discovered as a novel class of inhibitors for glycogen | + | Acyl ureas were discovered as a novel class of inhibitors for glycogen phosphorylase, a molecular target to control hyperglycemia in type 2 diabetics. This series is exemplified by 6-{2,6-Dichloro- 4-[3-(2-chloro-benzoyl)-ureido]-phenoxy}-hexanoic acid, which inhibits human liver glycogen phosphorylase a with an IC(50) of 2.0 microM. Here we analyze four crystal structures of acyl urea derivatives in complex with rabbit muscle glycogen phosphorylase b to elucidate the mechanism of inhibition of these inhibitors. The structures were determined and refined to 2.26 Angstroms resolution and demonstrate that the inhibitors bind at the allosteric activator site, where the physiological activator AMP binds. Acyl ureas induce conformational changes in the vicinity of the allosteric site. Our findings suggest that acyl ureas inhibit glycogen phosphorylase by direct inhibition of AMP binding and by indirect inhibition of substrate binding through stabilization of the T' state. |
==About this Structure== | ==About this Structure== | ||
| - | 1WUT 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 PLP and BN2 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:// | + | 1WUT 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=PLP:'>PLP</scene> and <scene name='pdbligand=BN2:'>BN2</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=1WUT OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Brachvogel, V.]] | [[Category: Brachvogel, V.]] | ||
| - | [[Category: Burger, H | + | [[Category: Burger, H J.]] |
[[Category: Defossa, E.]] | [[Category: Defossa, E.]] | ||
| - | [[Category: Herling, A | + | [[Category: Herling, A W.]] |
[[Category: Kadereit, D.]] | [[Category: Kadereit, D.]] | ||
[[Category: Klabunde, T.]] | [[Category: Klabunde, T.]] | ||
| - | [[Category: Kosmopoulou, M | + | [[Category: Kosmopoulou, M N.]] |
| - | [[Category: Oikonomakos, N | + | [[Category: Oikonomakos, N G.]] |
| - | [[Category: Roedern, E | + | [[Category: Roedern, E von.]] |
[[Category: Sarubbi, E.]] | [[Category: Sarubbi, E.]] | ||
[[Category: Schmoll, D.]] | [[Category: Schmoll, D.]] | ||
[[Category: Schonafinger, K.]] | [[Category: Schonafinger, K.]] | ||
| - | [[Category: Wendt, K | + | [[Category: Wendt, K U.]] |
[[Category: BN2]] | [[Category: BN2]] | ||
[[Category: PLP]] | [[Category: PLP]] | ||
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[[Category: type 2 diabetes]] | [[Category: type 2 diabetes]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:48:18 2008'' |
Revision as of 13:48, 21 February 2008
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Acyl Ureas as Human Liver Glycogen Phosphorylase Inhibitors for the Treatment of Type 2 Diabetes
Overview
Acyl ureas were discovered as a novel class of inhibitors for glycogen phosphorylase, a molecular target to control hyperglycemia in type 2 diabetics. This series is exemplified by 6-{2,6-Dichloro- 4-[3-(2-chloro-benzoyl)-ureido]-phenoxy}-hexanoic acid, which inhibits human liver glycogen phosphorylase a with an IC(50) of 2.0 microM. Here we analyze four crystal structures of acyl urea derivatives in complex with rabbit muscle glycogen phosphorylase b to elucidate the mechanism of inhibition of these inhibitors. The structures were determined and refined to 2.26 Angstroms resolution and demonstrate that the inhibitors bind at the allosteric activator site, where the physiological activator AMP binds. Acyl ureas induce conformational changes in the vicinity of the allosteric site. Our findings suggest that acyl ureas inhibit glycogen phosphorylase by direct inhibition of AMP binding and by indirect inhibition of substrate binding through stabilization of the T' state.
About this Structure
1WUT is a Single protein structure of sequence from Oryctolagus cuniculus with and as ligands. Active as Phosphorylase, with EC number 2.4.1.1 Full crystallographic information is available from OCA.
Reference
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
Page seeded by OCA on Thu Feb 21 15:48:18 2008
Categories: Oryctolagus cuniculus | Phosphorylase | Single protein | Brachvogel, V. | Burger, H J. | Defossa, E. | Herling, A W. | Kadereit, D. | Klabunde, T. | Kosmopoulou, M N. | Oikonomakos, N G. | Roedern, E von. | Sarubbi, E. | Schmoll, D. | Schonafinger, K. | Wendt, K U. | BN2 | PLP | Glycogenolysis | Type 2 diabetes
