Letters in Drug Design & Discovery

G. Perry
University of Texas
San Antonio, TX
USA
Email: lddd@benthamscience.org

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Indirubin-3-Aminooxy-Acetate Inhibits Glycogen Phosphorylase by Binding at the Inhibitor and the Allosteric Site. Broad Specificities of the Two Sites

Author(s): Magda N. Kosmopoulou, Demetres D. Leonidas, Evangelia D. Chrysina, Gerhard Eisenbrand, Nikos G. Oikonomakos.

Abstract:

The binding of the indirubin analogue indirubin-3-aminooxy-acetate (E243) to glycogen phosphorylase (GP) has been studied by kinetic and crystallographic experiments. E243 was shown to be a competitive inhibitor of GPb with respect to both Glc-1-P and AMP (Ki values of 21 ± 7 μM and 16 ± 3 μM, respectively). The crystal structure of the GPb-E243 complex determined at 1.9 Å resolution showed one ligand molecule bound at the inhibitor site, mainly by intercalating between the two aromatic side chains of Phe285 and Tyr613. In addition, two E243 molecules, Mol 1 and Mol 2, were bound at the allosteric activator AMP binding site and a new sub-site in the vicinity of the allosteric site, respectively, with their indole-aminooxyacetate rings inclined approximately 40°. The binding mode of E243 to GPb inhibitor and allosteric site is different from those of flavopiridol, AMP, Glc-6-P, W1807, and a potent phenoxy-phthalate compound, previously described, illustrating how the enzyme can accommodate a number of diverse chemical entities.

Keywords: type diabetes, glycogen phosphorylase, indirubin-aminooxy-acetate, inhibition, x-ray crystallography

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Article Details

VOLUME: 2
ISSUE: 5
Year: 2005
Page: [377 - 390]
Pages: 14
DOI: 10.2174/1570180054405839
Price: $58