The 1.76 Å Resolution Crystal Structure of Glycogen Phosphorylase b Complexed with Glucose, and CP320626, a Potential Antidiabetic Drug Original Research Article

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 Å resolution, and refined to a crystallographic R value of 0.211 (Rfree=0.235). CP320626 binds at a novel allosteric site, which is some 33 Å 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.