1p2d
Crystal Structure of Glycogen Phosphorylase B in complex with Beta Cyclodextrin
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OverviewOverview
A number of regulatory binding sites of glycogen phosphorylase (GP), such, as the catalytic, the inhibitor, and the new allosteric sites are, currently under investigation as targets for inhibition of hepatic, glycogenolysis under high glucose concentrations; in some cases specific, inhibitors are under evaluation in human clinical trials for therapeutic, intervention in type 2 diabetes. In an attempt to investigate whether the, storage site can be exploited as target for modulating hepatic glucose, production, alpha-, beta-, and gamma-cyclodextrins were identified as, moderate mixed-type competitive inhibitors of GPb (with respect to, glycogen) with K(i) values of 47.1, 14.1, and 7.4 mM, respectively. To, elucidate the structural basis of inhibition, we determined the structure, of GPb complexed with beta- and gamma-cyclodextrins at 1.94 A and 2.3 A, resolution, respectively. The structures of the two complexes reveal that, the inhibitors can be accommodated in the glycogen storage site of T-state, GPb with very little change of the tertiary structure and provide a basis, for understanding their potency and subsite specificity. Structural, comparisons of the two complexes with GPb in complex with either, maltopentaose (G5) or maltoheptaose (G7) show that beta- and, gamma-cyclodextrins bind in a mode analogous to the G5 and G7 binding with, only some differences imposed by their cyclic conformations. It appears, that the binding energy for stabilization of enzyme complexes derives from, hydrogen bonding and van der Waals contacts to protein residues. The, binding of alpha-cyclodextrin and octakis, (2,3,6-tri-O-methyl)-gamma-cyclodextrin was also investigated, but none of, them was bound in the crystal; moreover, the latter did not inhibit the, phosphorylase reaction.
About this StructureAbout this Structure
1P2D is a Single protein structure of sequence from Oryctolagus cuniculus with PLP as ligand. Active as Phosphorylase, with EC number 2.4.1.1 Full crystallographic information is available from OCA.
ReferenceReference
The binding of beta- and gamma-cyclodextrins to glycogen phosphorylase b: kinetic and crystallographic studies., Pinotsis N, Leonidas DD, Chrysina ED, Oikonomakos NG, Mavridis IM, Protein Sci. 2003 Sep;12(9):1914-24. PMID:12930991
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