3T3D

Glycogen phosphorylase b in complex with GlcU

Summary for 3T3D

• Entry DOI: 10.2210/pdb3t3d/pdb
• Related: 3SYM 3SYR
• Descriptor: Glycogen phosphorylase, muscle form, 1-beta-D-glucopyranosylpyrimidine-2,4(1H,3H)-dione (3 entities in total)
• Functional Keywords: a+b protein, transferase, muscle, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Oryctolagus cuniculus (European rabbit,Japanese white rabbit,domestic rabbit,rabbits)
• Total number of polymer chains: 1
• Total formula weight: 97793.55

Authors

Kantsadi, A.L.,Skamnaki, V.T.,Leonidas, D.D. (deposition date: 2011-07-25, release date: 2012-02-15, Last modification date: 2023-12-06)

Primary citation

Kantsadi, A.L.,Hayes, J.M.,Manta, S.,Skamnaki, V.T.,Kiritsis, C.,Psarra, A.M.,Koutsogiannis, Z.,Dimopoulou, A.,Theofanous, S.,Nikoleousakos, N.,Zoumpoulakis, P.,Kontou, M.,Papadopoulos, G.,Zographos, S.E.,Komiotis, D.,Leonidas, D.D.
The sigma-Hole Phenomenon of Halogen Atoms Forms the Structural Basis of the Strong Inhibitory Potency of C5 Halogen Substituted Glucopyranosyl Nucleosides towards Glycogen Phosphorylase  b
Chemmedchem, 7:722-732, 2012

PubMed Abstract: C5 halogen substituted glucopyranosyl nucleosides (1-(β-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 μM. The ability of the halogen atom to form intermolecular electrostatic interactions through the σ-hole phenomenon rather than through steric effects alone forms the structural basis of their improved inhibitory potential relative to the unsubstituted 1-(β-D-glucopyranosyl)uracil (K(i) =12.39 μM), 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.

PubMed: 22267166
DOI: 10.1002/cmdc.201100533

Experimental method

X-RAY DIFFRACTION (2.5 Å)