5N6S

Thermotoga maritima family 1 Glycoside hydrolase complexed with Carba-Cyclophellitol transition state mimic

Summary for 5N6S

• Entry DOI: 10.2210/pdb5n6s/pdb
• Descriptor: Beta-glucosidase A, 1,2-ETHANEDIOL, CHLORIDE ION, ... (9 entities in total)
• Functional Keywords: hydrolase, carba-cyclophellitol, mimic
• Biological source: Thermotoga maritima
• Total number of polymer chains: 4
• Total formula weight: 218903.50

Authors

Offen, W.,Davies, G. (deposition date: 2017-02-16, release date: 2017-03-01, Last modification date: 2024-01-17)

Primary citation

Beenakker, T.J.M.,Wander, D.P.A.,Offen, W.A.,Artola, M.,Raich, L.,Ferraz, M.J.,Li, K.Y.,Houben, J.H.P.M.,van Rijssel, E.R.,Hansen, T.,van der Marel, G.A.,Codee, J.D.C.,Aerts, J.M.F.G.,Rovira, C.,Davies, G.J.,Overkleeft, H.S.
Carba-cyclophellitols Are Neutral Retaining-Glucosidase Inhibitors.
J. Am. Chem. Soc., 139:6534-6537, 2017

PubMed Abstract: The conformational analysis of glycosidases affords a route to their specific inhibition through transition-state mimicry. Inspired by the rapid reaction rates of cyclophellitol and cyclophellitol aziridine-both covalent retaining β-glucosidase inhibitors-we postulated that the corresponding carba "cyclopropyl" analogue would be a potent retaining β-glucosidase inhibitor for those enzymes reacting through the H transition-state conformation. Ab initio metadynamics simulations of the conformational free energy landscape for the cyclopropyl inhibitors show a strong bias for the H conformation, and carba-cyclophellitol, with an N-(4-azidobutyl)carboxamide moiety, proved to be a potent inhibitor (K = 8.2 nM) of the Thermotoga maritima TmGH1 β-glucosidase. 3-D structural analysis and comparison with unreacted epoxides show that this compound indeed binds in the H conformation, suggesting that conformational strain induced through a cyclopropyl unit may add to the armory of tight-binding inhibitor designs.

PubMed: 28463498
DOI: 10.1021/jacs.7b01773

Experimental method

X-RAY DIFFRACTION (2.1 Å)