6U77
yGsy2p in complex with small molecule
Summary for 6U77
| Entry DOI | 10.2210/pdb6u77/pdb |
| Descriptor | 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) |
| Functional Keywords | inhibitor, glycogen synthase, transferase, transferase-inhibitor complex, transferase/inhibitor |
| Biological source | Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast) |
| Total number of polymer chains | 4 |
| Total formula weight | 323232.02 |
| Authors | Tang, B.,Hurley, T.D. (deposition date: 2019-08-31, release date: 2020-03-18, Last modification date: 2023-10-11) |
| Primary citation | 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 Cited by 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: 32134266DOI: 10.1021/acs.jmedchem.9b01851 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.85 Å) |
Structure validation
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