6U77

yGsy2p in complex with small molecule

6U77 の概要

• エントリーDOI: 10.2210/pdb6u77/pdb
• 分子名称: Glycogen [starch] synthase isoform 2, 6-O-phosphono-alpha-D-glucopyranose, 2-methoxy-4-(1-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-4-phenyl-1H-imidazol-5-yl)phenol (3 entities in total)
• 機能のキーワード: inhibitor, glycogen synthase, transferase, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 323232.02

構造登録者

Tang, B.,Hurley, T.D. (登録日: 2019-08-31, 公開日: 2020-03-18, 最終更新日: 2023-10-11)

主引用文献

Tang, B.,Frasinyuk, M.S.,Chikwana, V.M.,Mahalingan, K.K.,Morgan, C.A.,Segvich, D.M.,Bondarenko, S.P.,Mrug, G.P.,Wyrebek, P.,Watt, D.S.,DePaoli-Roach, A.A.,Roach, P.J.,Hurley, T.D.
Discovery and Development of Small-Molecule Inhibitors of Glycogen Synthase.
J.Med.Chem., 63:3538-3551, 2020

PubMed Abstract: The overaccumulation of glycogen appears as a hallmark in various glycogen storage diseases (GSDs), including Pompe, Cori, Andersen, and Lafora disease. Accumulating evidence suggests that suppression of glycogen accumulation represents a potential therapeutic approach for treating these GSDs. Using a fluorescence polarization assay designed to screen for inhibitors of the key glycogen synthetic enzyme, glycogen synthase (GS), we identified a substituted imidazole, ()-2-methoxy-4-(1-(2-(1-methylpyrrolidin-2-yl)ethyl)-4-phenyl-1-imidazol-5-yl)phenol (), as a first-in-class inhibitor for yeast GS 2 (yGsy2p). Data from X-ray crystallography at 2.85 Å, as well as kinetic data, revealed that bound within the uridine diphosphate glucose binding pocket of yGsy2p. The high conservation of residues between human and yeast GS in direct contact with informed the development of around 500 analogs. These analogs produced a structure-activity relationship profile that led to the identification of a substituted pyrazole, 4-(4-(4-hydroxyphenyl)-3-(trifluoromethyl)-1-pyrazol-5-yl)pyrogallol, with a 300-fold improved potency against human GS. These substituted pyrazoles possess a promising scaffold for drug development efforts targeting GS activity in GSDs associated with excess glycogen accumulation.

PubMed: 32134266
DOI: 10.1021/acs.jmedchem.9b01851

実験手法

X-RAY DIFFRACTION (2.85 Å)