|
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 |
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