3T3D

Glycogen phosphorylase b in complex with GlcU

3T3D の概要

• エントリーDOI: 10.2210/pdb3t3d/pdb
• 関連するPDBエントリー: 3SYM 3SYR
• 分子名称: Glycogen phosphorylase, muscle form, 1-beta-D-glucopyranosylpyrimidine-2,4(1H,3H)-dione (3 entities in total)
• 機能のキーワード: a+b protein, transferase, muscle, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Oryctolagus cuniculus (European rabbit,Japanese white rabbit,domestic rabbit,rabbits)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 97793.55

構造登録者

Kantsadi, A.L.,Skamnaki, V.T.,Leonidas, D.D. (登録日: 2011-07-25, 公開日: 2012-02-15, 最終更新日: 2023-12-06)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.5 Å)