2QRQ

Glycogen Phosphorylase b in complex with (1R)-3'-(4-methylphenyl)-spiro[1,5-anhydro-D-glucitol-1,5'-isoxazoline]

2QRQ の概要

• エントリーDOI: 10.2210/pdb2qrq/pdb
• 関連するPDBエントリー: 2QRM 2QRP
• 分子名称: Glycogen phosphorylase, muscle form, (3S,5R,7R,8S,9S,10R)-7-(hydroxymethyl)-3-(4-methylphenyl)-1,6-dioxa-2-azaspiro[4.5]decane-8,9,10-triol, DIMETHYL SULFOXIDE, ... (4 entities in total)
• 機能のキーワード: glycogenolysis, type 2 diabetes, acetylation, allosteric enzyme, carbohydrate metabolism, glycogen metabolism, glycosyltransferase, nucleotide-binding, phosphorylation, pyridoxal phosphate, 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: 99080.78

構造登録者

Gizilis, G.,Alexacou, K.M.,Chrysina, E.D.,Zographos, S.E.,Leonidas, D.D.,Oikonomakos, N.G. (登録日: 2007-07-28, 公開日: 2008-07-29, 最終更新日: 2024-04-03)

主引用文献

Benltifa, M.,Hayes, J.M.,Vidal, S.,Gueyrard, D.,Goekjian, P.G.,Praly, J.P.,Kizilis, G.,Tiraidis, C.,Alexacou, K.M.,Chrysina, E.D.,Zographos, S.E.,Leonidas, D.D.,Archontis, G.,Oikonomakos, N.G.
Glucose-based spiro-isoxazolines: a new family of potent glycogen phosphorylase inhibitors.
Bioorg.Med.Chem., 17:7368-7380, 2009

PubMed Abstract: A series of glucopyranosylidene-spiro-isoxazolines was prepared through regio- and stereoselective [3+2]-cycloaddition between the methylene acetylated exo-glucal and aromatic nitrile oxides. The deprotected cycloadducts were evaluated as inhibitors of muscle glycogen phosphorylase b. The carbohydrate-based family of five inhibitors displays K(i) values ranging from 0.63 to 92.5 microM. The X-ray structures of the enzyme-ligand complexes show that the inhibitors bind preferentially at the catalytic site of the enzyme retaining the less active T-state conformation. Docking calculations with GLIDE in extra-precision (XP) mode yielded excellent agreement with experiment, as judged by comparison of the predicted binding modes of the five ligands with the crystallographic conformations and the good correlation between the docking scores and the experimental free binding energies. Use of docking constraints on the well-defined positions of the glucopyranose moiety in the catalytic site and redocking of GLIDE-XP poses using electrostatic potential fit-determined ligand partial charges in quantum polarized ligand docking (QPLD) produced the best results in this regard.

PubMed: 19781947
DOI: 10.1016/j.bmc.2009.08.060

実験手法

X-RAY DIFFRACTION (1.8 Å)