2G9V

The crystal structure of glycogen phosphorylase in complex with (3R,4R,5R)-5-hydroxymethylpiperidine-3,4-diol and phosphate

2G9V の概要

• エントリーDOI: 10.2210/pdb2g9v/pdb
• 関連するPDBエントリー: 2g9q 2g9r 2g9u
• 分子名称: Glycogen phosphorylase, muscle form, PHOSPHATE ION, 5-HYDROXYMETHYL-3,4-DIHYDROXYPIPERIDINE, ... (4 entities in total)
• 機能のキーワード: glycogen phosphorylase, catalytic site, rational inhibitor design, 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: 97856.43

構造登録者

Oikonomakos, N.G.,Tiraidis, C.,Leonidas, D.D.,Zographos, S.E. (登録日: 2006-03-07, 公開日: 2007-01-16, 最終更新日: 2023-11-15)

主引用文献

Oikonomakos, N.G.,Tiraidis, C.,Leonidas, D.D.,Zographos, S.E.,Kristiansen, M.,Jessen, C.U.,Norskov-Lauritsen, L.,Agius, L.
Iminosugars as potential inhibitors of glycogenolysis: structural insights into the molecular basis of glycogen phosphorylase inhibition.
J.Med.Chem., 49:5687-5701, 2006

PubMed Abstract: Iminosugars DAB (5), isofagomine (9), and several N-substituted derivatives have been identified as potent inhibitors of liver glycogen phosphorylase a (IC(50) = 0.4-1.2 microM) and of basal and glucagon-stimulated glycogenolysis (IC(50) = 1-3 microM). The X-ray structures of 5, 9, and its N-3-phenylpropyl analogue 8 in complex with rabbit muscle glycogen phosphorylase (GPb) shows that iminosugars bind tightly at the catalytic site in the presence of the substrate phosphate and induce conformational changes that characterize the R-state conformation of the enzyme. Charged nitrogen N1 is within hydrogen-bonding distance with the carbonyl oxygen of His377 (5) and in ionic contact with the substrate phosphate oxygen (8 and 9). Our findings suggest that the inhibitors function as oxocarbenium ion transition-state analogues. The conformational change to the R state provides an explanation for previous findings that 5, unlike inhibitors that favor the T state, promotes phosphorylation of GPb in hepatocytes with sequential inactivation of glycogen synthase.

PubMed: 16970395
DOI: 10.1021/jm060496g

実験手法

X-RAY DIFFRACTION (2.15 Å)