PDBsum entry 2j79

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protein ligands metals Protein-protein interface(s) links
Hydrolase PDB id
Jmol PyMol
Protein chains
437 a.a. *
GTL ×2
Waters ×688
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Beta-glucosidase from thermotoga maritima in complex with galacto-hydroximolactam
Structure: Beta-glucosidase a. Chain: a, b. Fragment: residues 2-446. Synonym: gentiobiase, cellobiase, beta-d-glucoside, glucohydrolase, beta-glucosidase. Engineered: yes
Source: Thermotoga maritima. Organism_taxid: 2336. Expressed in: escherichia coli. Expression_system_taxid: 511693.
1.94Å     R-factor:   0.189     R-free:   0.242
Authors: T.M.Gloster,D.Zechel,A.Vasella,G.J.Davies
Key ref: T.M.Gloster et al. (2007). Glycosidase inhibition: an assessment of the binding of 18 putative transition-state mimics. J Am Chem Soc, 129, 2345-2354. PubMed id: 17279749
06-Oct-06     Release date:   18-Oct-06    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
Q08638  (BGLA_THEMA) -  Beta-glucosidase A
446 a.a.
437 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.  - Beta-glucosidase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Hydrolysis of terminal, non-reducing beta-D-glucose residues with release of beta-D-glucose.
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     metabolic process   4 terms 
  Biochemical function     hydrolase activity     5 terms  


J Am Chem Soc 129:2345-2354 (2007)
PubMed id: 17279749  
Glycosidase inhibition: an assessment of the binding of 18 putative transition-state mimics.
T.M.Gloster, P.Meloncelli, R.V.Stick, D.Zechel, A.Vasella, G.J.Davies.
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.

Literature references that cite this PDB file's key reference

  PubMed id Reference
21345211 S.Khan, T.Pozzo, M.Megyeri, S.Lindahl, A.Sundin, C.Turner, and E.N.Karlsson (2011).
Aglycone specificity of Thermotoga neapolitana β-glucosidase 1A modified by mutagenesis, leading to increased catalytic efficiency in quercetin-3-glucoside hydrolysis.
  BMC Biochem, 12, 11.  
21420868 T.Li, L.Guo, Y.Zhang, J.Wang, Z.Zhang, J.Li, W.Zhang, J.Lin, W.Zhao, and P.G.Wang (2011).
Structure-activity relationships in a series of C2-substituted gluco-configured tetrahydroimidazopyridines as β-glucosidase inhibitors.
  Bioorg Med Chem, 19, 2136-2144.  
20689974 Y.He, A.K.Bubb, K.A.Stubbs, T.M.Gloster, and G.J.Davies (2011).
Inhibition of a bacterial O-GlcNAcase homologue by lactone and lactam derivatives: structural, kinetic and thermodynamic analyses.
  Amino Acids, 40, 829-839.
PDB codes: 2xm1 2xm2
20665773 A.Lammerts van Bueren, S.D.Popat, C.H.Lin, and G.J.Davies (2010).
Structural and thermodynamic analyses of α-L-fucosidase inhibitors.
  Chembiochem, 11, 1971-1974.
PDB codes: 2xib 2xii
20714463 D.J.Wardrop, and S.L.Waidyarachchi (2010).
Synthesis and biological activity of naturally occurring α-glucosidase inhibitors.
  Nat Prod Rep, 27, 1431-1468.  
20490603 J.R.Ketudat Cairns, and A.Esen (2010).
  Cell Mol Life Sci, 67, 3389-3405.  
20851343 M.S.Macauley, Y.He, T.M.Gloster, K.A.Stubbs, G.J.Davies, and D.J.Vocadlo (2010).
Inhibition of O-GlcNAcase using a potent and cell-permeable inhibitor does not induce insulin resistance in 3T3-L1 adipocytes.
  Chem Biol, 17, 937-948.
PDB code: 2xj7
20396401 T.M.Gloster, and D.J.Vocadlo (2010).
Mechanism, Structure, and Inhibition of O-GlcNAc Processing Enzymes.
  Curr Signal Transduct Ther, 5, 74-91.  
20066263 T.M.Gloster, and G.J.Davies (2010).
Glycosidase inhibition: assessing mimicry of the transition state.
  Org Biomol Chem, 8, 305-320.  
19579240 J.Calveras, M.Egido-Gabás, L.Gómez, J.Casas, T.Parella, J.Joglar, J.Bujons, and P.Clapés (2009).
Dihydroxyacetone phosphate aldolase catalyzed synthesis of structurally diverse polyhydroxylated pyrrolidine derivatives and evaluation of their glycosidase inhibitory properties.
  Chemistry, 15, 7310-7328.  
19532990 M.Aguilar-Moncayo, T.M.Gloster, J.P.Turkenburg, M.I.García-Moreno, C.Ortiz Mellet, G.J.Davies, and J.M.García Fernández (2009).
Glycosidase inhibition by ring-modified castanospermine analogues: tackling enzyme selectivity by inhibitor tailoring.
  Org Biomol Chem, 7, 2738-2747.
PDB codes: 2wbg 2wc3 2wc4
19072093 M.T.Yang, and K.A.Woerpel (2009).
The effect of electrostatic interactions on conformational equilibria of multiply substituted tetrahydropyran oxocarbenium ions.
  J Org Chem, 74, 545-553.  
18822375 B.Henrissat, G.Sulzenbacher, and Y.Bourne (2008).
Glycosyltransferases, glycoside hydrolases: surprise, surprise!
  Curr Opin Struct Biol, 18, 527-533.  
18558099 D.J.Vocadlo, and G.J.Davies (2008).
Mechanistic insights into glycosidase chemistry.
  Curr Opin Chem Biol, 12, 539-555.  
18408714 L.E.Tailford, W.A.Offen, N.L.Smith, C.Dumon, C.Morland, J.Gratien, M.P.Heck, R.V.Stick, Y.Blériot, A.Vasella, H.J.Gilbert, and G.J.Davies (2008).
Structural and biochemical evidence for a boat-like transition state in beta-mannosidases.
  Nat Chem Biol, 4, 306-312.
PDB codes: 2vjx 2vl4 2vmf 2vo5 2vot 2vqt 2vqu 2vr4
18076078 N.S.Kumar, D.A.Kuntz, X.Wen, B.M.Pinto, and D.R.Rose (2008).
Binding of sulfonium-ion analogues of di-epi-swainsonine and 8-epi-lentiginosine to Drosophila Golgi alpha-mannosidase II: the role of water in inhibitor binding.
  Proteins, 71, 1484-1496.
PDB codes: 2ow6 2ow7
18292875 V.A.Money, A.Cartmell, C.I.Guerreiro, V.M.Ducros, C.M.Fontes, H.J.Gilbert, and G.J.Davies (2008).
Probing the beta-1,3:1,4 glucanase, CtLic26A, with a thio-oligosaccharide and enzyme variants.
  Org Biomol Chem, 6, 851-853.
PDB code: 2vi0
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