The 1.76 A resolution crystal structure of glycogen phosphorylase B complexed with glucose, and CP320626, a potential antidiabetic drug

Bioorg Med Chem. 2002 May;10(5):1313-9. doi: 10.1016/s0968-0896(01)00394-7.

Abstract

CP320626, a potential antidiabetic drug, inhibits glycogen phosphorylase in synergism with glucose. To elucidate the structural basis of synergistic inhibition, we determined the structure of muscle glycogen phosphorylase b (MGPb) complexed with both glucose and CP320626 at 1.76 A resolution, and refined to a crystallographic R value of 0.211 (R(free)=0.235). CP320626 binds at a novel allosteric site, which is some 33 A from the catalytic site, where glucose binds. The high resolution structure allows unambiguous definition of the conformation of the 1-acetyl-4-hydroxy-piperidine ring supported by theoretical energy calculations. Both CP320626 and glucose promote the less active T-state, thereby explaining their synergistic inhibition. Structural comparison of MGPb--glucose--CP320626 complex with liver glycogen phosphorylase a (LGPa) complexed with a related compound (CP403700) show that the ligand binding site is conserved in LGPa.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Site
  • Amides / chemistry*
  • Catalytic Domain
  • Crystallography, X-Ray
  • Drug Synergism
  • Enzyme Inhibitors / chemistry
  • Glucose / chemistry*
  • Glucose / metabolism
  • Glycogen Phosphorylase, Muscle Form / chemistry*
  • Glycogen Phosphorylase, Muscle Form / metabolism
  • Humans
  • Hypoglycemic Agents / chemistry*
  • Indoles / chemistry*
  • Models, Molecular
  • Molecular Structure
  • Protein Binding
  • Protein Conformation

Substances

  • Amides
  • Enzyme Inhibitors
  • Hypoglycemic Agents
  • Indoles
  • Glycogen Phosphorylase, Muscle Form
  • CP 320626
  • Glucose