5NPF

Crystal structure of txGH116 (beta-glucosidase from Thermoanaerobacterium xylolyticum) in complex with beta Cyclophellitol Cyclosulfate probe ME594

Summary for 5NPF

• Entry DOI: 10.2210/pdb5npf/pdb
• Descriptor: Glucosylceramidase, 1,2-ETHANEDIOL, CALCIUM ION, ... (5 entities in total)
• Functional Keywords: hydrolase
• Biological source: Thermoanaerobacterium xylanolyticum
• Total number of polymer chains: 1
• Total formula weight: 92844.32

Authors

Wu, L.,Offen, W.A.,Breen, I.Z.,Davies, G.J. (deposition date: 2017-04-16, release date: 2017-08-09, Last modification date: 2024-01-17)

Primary citation

Artola, M.,Wu, L.,Ferraz, M.J.,Kuo, C.L.,Raich, L.,Breen, I.Z.,Offen, W.A.,Codee, J.D.C.,van der Marel, G.A.,Rovira, C.,Aerts, J.M.F.G.,Davies, G.J.,Overkleeft, H.S.
1,6-Cyclophellitol Cyclosulfates: A New Class of Irreversible Glycosidase Inhibitor.
ACS Cent Sci, 3:784-793, 2017

PubMed Abstract: The essential biological roles played by glycosidases, coupled to the diverse therapeutic benefits of pharmacologically targeting these enzymes, provide considerable motivation for the development of new inhibitor classes. Cyclophellitol epoxides and aziridines are recently established covalent glycosidase inactivators. Inspired by the application of cyclic sulfates as electrophilic equivalents of epoxides in organic synthesis, we sought to test whether cyclophellitol cyclosulfates would similarly act as irreversible glycosidase inhibitors. Here we present the synthesis, conformational analysis, and application of novel 1,6-cyclophellitol cyclosulfates. We show that 1,6--cyclophellitol cyclosulfate (α-cyclosulfate) is a rapidly reacting α-glucosidase inhibitor whose C chair conformation matches that adopted by α-glucosidase Michaelis complexes. The 1,6-cyclophellitol cyclosulfate (β-cyclosulfate) reacts more slowly, likely reflecting its conformational restrictions. Selective glycosidase inhibitors are invaluable as mechanistic probes and therapeutic agents, and we propose cyclophellitol cyclosulfates as a valuable new class of carbohydrate mimetics for application in these directions.

PubMed: 28776021
DOI: 10.1021/acscentsci.7b00214

Experimental method

X-RAY DIFFRACTION (1.38 Å)