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

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 Angstrom 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 Angstrom 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 5320626 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. (C) 2002 Elsevier Science Ltd. All rights reserved.