2OFF

The crystal structure of Glycogen Phosphorylase b in complex with a potent allosteric inhibitor

2OFF の概要

• エントリーDOI: 10.2210/pdb2off/pdb
• 分子名称: Glycogen phosphorylase, muscle form, 2-DEOXY-3,4-BIS-O-[3-(4-HYDROXYPHENYL)PROPANOYL]-L-THREO-PENTARIC ACID (3 entities in total)
• 機能のキーワード: glycogenolysis, type 2 diabetes, transferase
• 由来する生物種: Oryctolagus cuniculus (rabbit)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 97975.72

構造登録者

Tiraidis, C.,Alexacou, K.-M.,Zographos, S.E.,Leonidas, D.D.,Gimisis, T.,Oikonomakos, N.G. (登録日: 2007-01-03, 公開日: 2007-08-07, 最終更新日: 2023-12-27)

主引用文献

Tiraidis, C.,Alexacou, K.-M.,Zographos, S.E.,Leonidas, D.D.,Gimisis, T.,Oikonomakos, N.G.
FR258900, a potential anti-hyperglycemic drug, binds at the allosteric site of glycogen phosphorylase
Protein Sci., 16:1773-1782, 2007

PubMed Abstract: FR258900 has been discovered as a novel inhibitor of human liver glycogen phosphorylase a and proved to suppress hepatic glycogen breakdown and reduce plasma glucose concentrations in diabetic mice models. To elucidate the mechanism of inhibition, we have determined the crystal structure of the cocrystallized rabbit muscle glycogen phosphorylase b-FR258900 complex and refined it to 2.2 A resolution. The structure demonstrates that the inhibitor binds at the allosteric activator site, where the physiological activator AMP binds. The contacts from FR258900 to glycogen phosphorylase are dominated by nonpolar van der Waals interactions with Gln71, Gln72, Phe196, and Val45' (from the symmetry-related subunit), and also by ionic interactions from the carboxylate groups to the three arginine residues (Arg242, Arg309, and Arg310) that form the allosteric phosphate-recognition subsite. The binding of FR258900 to the protein promotes conformational changes that stabilize an inactive T-state quaternary conformation of the enzyme. The ligand-binding mode is different from those of the potent phenoxy-phthalate and acyl urea inhibitors, previously described, illustrating the broad specificity of the allosteric site.

PubMed: 17600143
DOI: 10.1110/ps.072925607

実験手法

X-RAY DIFFRACTION (2.2 Å)