1WV1: Crystallographic Studies On Acyl Ureas, A New Class Of Inhibitors Of Glycogenphosphorylase. Broad Specificity Of The Allosteric Site

Acyl ureas were discovered as a novel class of inhibitors for glycogen phosphorylase, a molecular target to control hyperglycemia in type 2 diabetics. This series is exemplified by 6-{2,6-Dichloro- 4-[3-(2-chloro-benzoyl)-ureido]-phenoxy}-hexanoic acid, which inhibits human liver glycogen phosphorylase a with an IC(50) of 2.0 microM. Here we analyze four crystal structures of acyl urea derivatives in complex with rabbit muscle glycogen phosphorylase b to elucidate the mechanism of inhibition of these inhibitors. The structures were determined and refined to 2.26 Angstroms resolution and demonstrate that the inhibitors bind at the allosteric activator site, where the physiological activator AMP binds. Acyl ureas induce conformational changes in the vicinity of the allosteric site. Our findings suggest that acyl ureas inhibit glycogen phosphorylase by direct inhibition of AMP binding and by indirect inhibition of substrate binding through stabilization of the T' state.
PDB ID: 1WV1Download
MMDB ID: 36566
PDB Deposition Date: 2004/12/10
Updated in MMDB: 2007/10
Experimental Method:
x-ray diffraction
Resolution: 2.26  Å
Source Organism:
Similar Structures:
Biological Unit for 1WV1: dimeric; determined by author and by software (PISA,PQS)
Molecular Components in 1WV1
Label Count Molecule
Proteins (2 molecules)
Glycogen Phosphorylase, Muscle Form(Gene symbol: PYGM)
Molecule annotation
Chemicals (4 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB