1wv0
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(New page: 200px<br /><applet load="1wv0" size="450" color="white" frame="true" align="right" spinBox="true" caption="1wv0, resolution 2.26Å" /> '''Crystallographic stu...)
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Revision as of 03:34, 21 November 2007
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Crystallographic studies on acyl ureas, a new class of inhibitors of glycogen phosphorylase. Broad specificity of the allosteric site
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
1WV0 is a Single protein structure of sequence from Oryctolagus cuniculus with PLP and BN4 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
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