Structure-activity analysis of the purine binding site of human liver glycogen phosphorylase |
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Authors: | Ekstrom Jennifer L Pauly Thomas A Carty Maynard D Soeller Walter C Culp Jeff Danley Dennis E Hoover Dennis J Treadway Judith L Gibbs E Michael Fletterick Robert J Day Yasmina S N Myszka David G Rath Virginia L |
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Affiliation: | Exploratory Medicinal Sciences, Groton, CT 06340, USA. |
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Abstract: | Human liver glycogen phosphorylase (HLGP) catalyzes the breakdown of glycogen to maintain serum glucose levels and is a therapeutic target for diabetes. HLGP is regulated by multiple interacting allosteric sites, each of which is a potential drug binding site. We used surface plasmon resonance (SPR) to screen for compounds that bind to the purine allosteric inhibitor site. We determined the affinities of a series of compounds and solved the crystal structures of three representative ligands with K(D) values from 17-550 microM. The crystal structures reveal that the affinities are partly determined by ligand-specific water-mediated hydrogen bonds and side chain movements. These effects could not be predicted; both crystallographic and SPR studies were required to understand the important features of binding and together provide a basis for the design of new allosteric inhibitors targeting this site. |
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