2J79

Beta-glucosidase from Thermotoga maritima in complex with galacto- hydroximolactam

Summary for 2J79

• Entry DOI: 10.2210/pdb2j79/pdb
• Related: 1OD0 1OIF 1OIN 1UZ1 1W3J 2CBU 2CBV 2CES 2CET 2J75 2J77 2J78 2J7A 2J7B 2J7C 2J7D 2J7E 2J7F 2J7G 2J7H
• Descriptor: BETA-GLUCOSIDASE A, (2E,3R,4R,5R,6S)-3,4,5-TRIHYDROXY-6-(HYDROXYMETHYL)-2-PIPERIDINONE, ACETATE ION, ... (5 entities in total)
• Functional Keywords: family 1, hydrolase, inhibitor, glycosidase, polysaccharide degradation, transition state mimic, carbohydrate metabolism, glycoside hydrolase, cellulose degradation
• Biological source: THERMOTOGA MARITIMA
• Total number of polymer chains: 2
• Total formula weight: 108364.76

Authors

Gloster, T.M.,Zechel, D.,Vasella, A.,Davies, G.J. (deposition date: 2006-10-06, release date: 2006-10-18, Last modification date: 2023-12-13)

Primary citation

Gloster, T.M.,Meloncelli, P.,Stick, R.V.,Zechel, D.,Vasella, A.,Davies, G.J.
Glycosidase Inhibition: An Assessment of the Binding of 18 Putative Transition-State Mimics.
J.Am.Chem.Soc., 129:2345-, 2007

PubMed Abstract: The inhibition of glycoside hydrolases, through transition-state mimicry, is important both as a probe of enzyme mechanism and in the continuing quest for new drugs, notably in the treatment of cancer, HIV, influenza, and diabetes. The high affinity with which these enzymes are known to bind the transition state provides a framework upon which to design potent inhibitors. Recent work [for example, Bülow, A. et al. J. Am. Chem. Soc. 2000, 122, 8567-8568; Zechel, D. L. et al. J. Am. Chem. Soc. 2003, 125, 14313-14323] has revealed quite confusing and counter-intuitive patterns of inhibition for a number of glycosidase inhibitors. Here we describe a synergistic approach for analysis of inhibitors with a single enzyme 'model system', the Thermotoga maritima family 1 beta-glucosidase, TmGH1. The pH dependence of enzyme activity and inhibition has been determined, structures of inhibitor complexes have been solved by X-ray crystallography, with data up to 1.65 A resolution, and isothermal titration calorimetry was used to establish the thermodynamic signature. This has allowed the characterization of 18 compounds, all putative transition-state mimics, in order to build an 'inhibition profile' that provides an insight into what governs binding. In contrast to our preconceptions, there is little correlation of inhibitor chemistry with the calorimetric dissection of thermodynamics. The ensemble of inhibitors shows strong enthalpy-entropy compensation, and the random distribution of similar inhibitors across the plot of DeltaH degrees a vs TDeltaS degrees a likely reflects the enormous contribution of solvation and desolvation effects on ligand binding.

PubMed: 17279749
DOI: 10.1021/JA066961G

Experimental method

X-RAY DIFFRACTION (1.94 Å)