1wut: Difference between revisions

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[[Image:1wut.gif|left|200px]]
{{Seed}}
[[Image:1wut.png|left|200px]]


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{{STRUCTURE_1wut|  PDB=1wut  |  SCENE=  }}  
{{STRUCTURE_1wut|  PDB=1wut  |  SCENE=  }}  


'''Acyl Ureas as Human Liver Glycogen Phosphorylase Inhibitors for the Treatment of Type 2 Diabetes'''
===Acyl Ureas as Human Liver Glycogen Phosphorylase Inhibitors for the Treatment of Type 2 Diabetes===




==Overview==
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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.
The line below this paragraph, {{ABSTRACT_PUBMED_15987904}}, adds the Publication Abstract to the page
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{{ABSTRACT_PUBMED_15987904}}


==About this Structure==
==About this Structure==
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==Reference==
==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:[http://www.ncbi.nlm.nih.gov/pubmed/15987904 15987904]
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:[http://www.ncbi.nlm.nih.gov/pubmed/15987904 15987904]
A new allosteric site in glycogen phosphorylase b as a target for drug interactions., Oikonomakos NG, Skamnaki VT, Tsitsanou KE, Gavalas NG, Johnson LN, Structure. 2000 Jun 15;8(6):575-84. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/10873856 10873856]
The structure of glycogen phosphorylase b with an alkyldihydropyridine-dicarboxylic acid compound, a novel and potent inhibitor., Zographos SE, Oikonomakos NG, Tsitsanou KE, Leonidas DD, Chrysina ED, Skamnaki VT, Bischoff H, Goldmann S, Watson KA, Johnson LN, Structure. 1997 Nov 15;5(11):1413-25. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/9384557 9384557]
Human liver glycogen phosphorylase inhibitors bind at a new allosteric site., Rath VL, Ammirati M, Danley DE, Ekstrom JL, Gibbs EM, Hynes TR, Mathiowetz AM, McPherson RK, Olson TV, Treadway JL, Hoover DJ, Chem Biol. 2000 Sep;7(9):677-82. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/10980448 10980448]
A new class of glycogen phosphorylase inhibitors., Lu Z, Bohn J, Bergeron R, Deng Q, Ellsworth KP, Geissler WM, Harris G, McCann PE, McKeever B, Myers RW, Saperstein R, Willoughby CA, Yao J, Chapman K, Bioorg Med Chem Lett. 2003 Nov 17;13(22):4125-8. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/14592521 14592521]
[[Category: Oryctolagus cuniculus]]
[[Category: Oryctolagus cuniculus]]
[[Category: Phosphorylase]]
[[Category: Phosphorylase]]
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[[Category: Glycogenolysis]]
[[Category: Glycogenolysis]]
[[Category: Type 2 diabetes]]
[[Category: Type 2 diabetes]]
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