2J79

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


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.94 Å
  • R-Value Free: 0.242 
  • R-Value Work: 0.186 
  • R-Value Observed: 0.189 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Glycosidase Inhibition: An Assessment of the Binding of 18 Putative Transition-State Mimics.

Gloster, T.M.Meloncelli, P.Stick, R.V.Zechel, D.Vasella, A.Davies, G.J.

(2007) J Am Chem Soc 129: 2345

  • DOI: https://doi.org/10.1021/ja066961g
  • Primary Citation of Related Structures:  
    2J75, 2J77, 2J78, 2J79, 2J7B, 2J7C, 2J7D, 2J7E, 2J7F, 2J7G, 2J7H

  • 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.


  • Organizational Affiliation

    York Structural Biology Laboratory, Department of Chemistry, University of York, York YO10 5YW, UK.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
BETA-GLUCOSIDASE A
A, B
468Thermotoga maritimaMutation(s): 0 
EC: 3.2.1.21
UniProt
Find proteins for Q08638 (Thermotoga maritima (strain ATCC 43589 / DSM 3109 / JCM 10099 / NBRC 100826 / MSB8))
Explore Q08638 
Go to UniProtKB:  Q08638
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ08638
Sequence Annotations
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  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
GTL PDBBind:  2J79 Kd: 1100 (nM) from 1 assay(s)
Binding MOAD:  2J79 Kd: 1100 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.94 Å
  • R-Value Free: 0.242 
  • R-Value Work: 0.186 
  • R-Value Observed: 0.189 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 94.157α = 90
b = 94.436β = 90
c = 113.305γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
DENZOdata reduction
SCALEPACKdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2006-10-18
    Type: Initial release
  • Version 1.1: 2011-05-08
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2023-12-13
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description