Structure-activity analysis of the purine binding site of human liver glycogen phosphorylase

Chem Biol. 2002 Aug;9(8):915-24. doi: 10.1016/s1074-5521(02)00186-2.


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.

MeSH terms

  • Allosteric Site
  • Binding Sites
  • Crystallography, X-Ray
  • Diabetes Mellitus / drug therapy
  • Drug Evaluation, Preclinical / instrumentation
  • Drug Evaluation, Preclinical / methods
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Glycogen Phosphorylase / antagonists & inhibitors*
  • Humans
  • Hydrogen Bonding
  • Ligands
  • Liver / enzymology
  • Molecular Structure
  • Purines / antagonists & inhibitors
  • Purines / metabolism*
  • Structure-Activity Relationship
  • Water / chemistry


  • Enzyme Inhibitors
  • Ligands
  • Purines
  • Water
  • Glycogen Phosphorylase