3MS2: Glycogen Phosphorylase Complexed With 4-Methylbenzaldehyde-4-(Beta-D- Glucopyranosyl) Thiosemicarbazone

Citation:
Abstract
Glycogen phosphorylase (GP) is a promising target for the treatment of type 2 diabetes. In the process of structure based drug design for GP, a group of 15 aromatic aldehyde 4-(beta-d-glucopyranosyl)thiosemicarbazones have been synthesized and evaluated as inhibitors of rabbit muscle glycogen phosphorylase b (GPb) by kinetic studies. These compounds are competitive inhibitors of GPb with respect to alpha-d-glucose-1-phosphate with IC(50) values ranging from 5.7 to 524.3muM. In order to elucidate the structural basis of their inhibition, the crystal structures of these compounds in complex with GPb at 1.95-2.23A resolution were determined. The complex structures reveal that the inhibitors are accommodated at the catalytic site with the glucopyranosyl moiety at approximately the same position as alpha-d-glucose and stabilize the T conformation of the 280s loop. The thiosemicarbazone part of the studied glucosyl thiosemicarbazones possess a moiety derived from substituted benzaldehydes with NO(2), F, Cl, Br, OH, OMe, CF(3), or Me at the ortho-, meta- or para-position of the aromatic ring as well as a moiety derived from 4-pyridinecarboxaldehyde. These fit tightly into the beta-pocket, a side channel from the catalytic site with no access to the bulk solvent. The differences in their inhibitory potency can be interpreted in terms of variations in the interactions of the aldehyde-derived moiety with protein residues in the beta-pocket. In addition, 14 out of the 15 studied inhibitors were found bound at the new allosteric site of the enzyme.
PDB ID: 3MS2Download
MMDB ID: 87697
PDB Deposition Date: 2010/4/29
Updated in MMDB: 2011/05
Experimental Method:
x-ray diffraction
Resolution: 2.1  Å
Source Organism:
Similar Structures:
Biological Unit for 3MS2: dimeric; determined by author and by software (PISA)
Molecular Components in 3MS2
Label Count Molecule
Proteins (2 molecules)
2
Glycogen Phosphorylase, Muscle Form(Gene symbol: PYGM)
Molecule annotation
Chemicals (4 molecules)
1
4
* Click molecule labels to explore molecular sequence information.

Citing MMDB
.