3T3G: Glycogen Phosphorylase b in complex with GlcBrU

Citation:
Abstract
C5 halogen substituted glucopyranosyl nucleosides (1-(beta-D-glucopyranosyl)-5-X-uracil; X=Cl, Br, I) have been discovered as some of the most potent active site inhibitors of glycogen phosphorylase (GP), with respective K(i) values of 1.02, 3.27, and 1.94 muM. The ability of the halogen atom to form intermolecular electrostatic interactions through the sigma-hole phenomenon rather than through steric effects alone forms the structural basis of their improved inhibitory potential relative to the unsubstituted 1-(beta-D-glucopyranosyl)uracil (K(i) =12.39 muM), as revealed by X-ray crystallography and modeling calculations exploiting quantum mechanics methods. Good agreement was obtained between kinetics results and relative binding affinities calculated by QM/MM-PBSA methodology for various substitutions at C5. Ex vivo experiments demonstrated that the most potent derivative (X=Cl) toward purified GP has no cytotoxicity and moderate inhibitory potency at the cellular level. In accordance, ADMET property predictions were performed, and suggest decreased polar surface areas as a potential means of improving activity in the cell.
PDB ID: 3T3GDownload
MMDB ID: 97261
PDB Deposition Date: 2011/7/25
Updated in MMDB: 2017/11
Experimental Method:
x-ray diffraction
Resolution: 2.4  Å
Source Organism:
Similar Structures:
Biological Unit for 3T3G: dimeric; determined by author and by software (PISA)
Molecular Components in 3T3G
Label Count Molecule
Proteins (2 molecules)
2
Glycogen Phosphorylase, Muscle Form(Gene symbol: PYGM)
Molecule annotation
Chemicals (2 molecules)
1
2
* Click molecule labels to explore molecular sequence information.

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