1wv1: Difference between revisions
New page: left|200px<br /><applet load="1wv1" size="450" color="white" frame="true" align="right" spinBox="true" caption="1wv1, resolution 2.26Å" /> '''Crystallographic stu... |
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[[Image:1wv1.gif|left|200px]]<br /><applet load="1wv1" size=" | [[Image:1wv1.gif|left|200px]]<br /><applet load="1wv1" size="350" color="white" frame="true" align="right" spinBox="true" | ||
caption="1wv1, resolution 2.26Å" /> | caption="1wv1, resolution 2.26Å" /> | ||
'''Crystallographic studies on acyl ureas, a new class of inhibitors of glycogenphosphorylase. Broad specificity of the allosteric site'''<br /> | '''Crystallographic studies on acyl ureas, a new class of inhibitors of glycogenphosphorylase. Broad specificity of the allosteric site'''<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== | ||
1WV1 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 BN5 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:// | 1WV1 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=BN5:'>BN5</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=1WV1 OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Phosphorylase]] | [[Category: Phosphorylase]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Chrysina, E | [[Category: Chrysina, E D.]] | ||
[[Category: Defossa, E.]] | [[Category: Defossa, E.]] | ||
[[Category: Klabunde, T.]] | [[Category: Klabunde, T.]] | ||
[[Category: Kosmopoulou, M | [[Category: Kosmopoulou, M N.]] | ||
[[Category: Leonidas, D | [[Category: Leonidas, D D.]] | ||
[[Category: Oikonomakos, N | [[Category: Oikonomakos, N G.]] | ||
[[Category: Wendt, K | [[Category: Wendt, K U.]] | ||
[[Category: BN5]] | [[Category: BN5]] | ||
[[Category: PLP]] | [[Category: PLP]] | ||
| Line 26: | Line 26: | ||
[[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 15:48:24 2008'' | ||
Revision as of 16:48, 21 February 2008
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Crystallographic studies on acyl ureas, a new class of inhibitors of glycogenphosphorylase. Broad specificity of the allosteric site
OverviewOverview
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 StructureAbout this Structure
1WV1 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.
ReferenceReference
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
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