5OSS

Beta-glucosidase from Thermotoga maritima in complex with Gluco-1H-imidazole

Summary for 5OSS

• Entry DOI: 10.2210/pdb5oss/pdb
• Descriptor: Beta-glucosidase A, 1,2-ETHANEDIOL, CHLORIDE ION, ... (6 entities in total)
• Functional Keywords: glycosylhydrolase, thermotoga maritima, glucoimidazole, hydrolase
• Biological source: Thermotoga maritima (strain ATCC 43589 / MSB8 / DSM 3109 / JCM 10099)
• Total number of polymer chains: 2
• Total formula weight: 108760.61

Authors

Offen, W.A.,Schroeder, S.P.,Davies, G.J.,Overkleeft, H.S. (deposition date: 2017-08-18, release date: 2018-04-11, Last modification date: 2024-01-17)

Primary citation

Schroder, S.P.,Wu, L.,Artola, M.,Hansen, T.,Offen, W.A.,Ferraz, M.J.,Li, K.Y.,Aerts, J.M.F.G.,van der Marel, G.A.,Codee, J.D.C.,Davies, G.J.,Overkleeft, H.S.
Gluco-1 H-imidazole: A New Class of Azole-Type beta-Glucosidase Inhibitor.
J. Am. Chem. Soc., 140:5045-5048, 2018

PubMed Abstract: Gluco-azoles competitively inhibit glucosidases by transition-state mimicry and their ability to interact with catalytic acid residues in glucosidase active sites. We noted that no azole-type inhibitors described, to date, possess a protic nitrogen characteristic for 1 H-imidazoles. Here, we present gluco-1 H-imidazole, a gluco-azole bearing a 1 H-imidazole fused to a glucopyranose-configured cyclitol core, and three close analogues as new glucosidase inhibitors. All compounds inhibit human retaining β-glucosidase, GBA1, with the most potent ones inhibiting this enzyme (deficient in Gaucher disease) on a par with glucoimidazole. None inhibit glucosylceramide synthase, cytosolic β-glucosidase GBA2 or α-glucosidase GAA. Structural, physical and computational studies provide first insights into the binding mode of this conceptually new class of retaining β-glucosidase inhibitors.

PubMed: 29601200
DOI: 10.1021/jacs.8b02399

Experimental method

X-RAY DIFFRACTION (1.7 Å)