type	Journal Article
authors	Oikonomakos, N. G.; Zographos, S. E.; Skamnaki, V. T.; Archontis, G.
title	The 1.76 A Resolution Crystal Structure of Glycogen Phosphorylase b Complexed with Glucose, and CP320626, a Potential Antidiabetic Drug
journal	Bioorg Med Chem
Activity	2.4.1.1
ui	21883609
year	(2002)
volume	10
number	5
pages	1313-9.
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.
last changed	2002/11/12 16:17