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PDBsum entry 2quo

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Toxin PDB id
2quo
Jmol
Contents
Protein chain
123 a.a.
Ligands
SO4
Waters ×202
PDB id:
2quo
Name: Toxin
Title: Crystal structure of c terminal fragment of clostridium perfringens enterotoxin
Structure: Heat-labile enterotoxin b chain. Chain: a. Fragment: c-cpe, c-terminal fragment 194-319. Engineered: yes
Source: Clostridium perfringens. Organism_taxid: 1502. Strain: f5603. Gene: cpe. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
1.75Å     R-factor:   0.199     R-free:   0.229
Authors: L.Betts,C.M.Van Itallie
Key ref:
C.M.Van Itallie et al. (2008). Structure of the claudin-binding domain of Clostridium perfringens enterotoxin. J Biol Chem, 283, 268-274. PubMed id: 17977833 DOI: 10.1074/jbc.M708066200
Date:
06-Aug-07     Release date:   30-Oct-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P01558  (ELTB_CLOPF) -  Heat-labile enterotoxin B chain
Seq:
Struc:
319 a.a.
123 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   1 term 
  Biological process     pathogenesis   1 term 

 

 
DOI no: 10.1074/jbc.M708066200 J Biol Chem 283:268-274 (2008)
PubMed id: 17977833  
 
 
Structure of the claudin-binding domain of Clostridium perfringens enterotoxin.
C.M.Van Itallie, L.Betts, J.G.Smedley, B.A.McClane, J.M.Anderson.
 
  ABSTRACT  
 
Clostridium perfringens enterotoxin is a common cause of food-borne and antibiotic-associated diarrhea. The toxin's receptors on intestinal epithelial cells include claudin-3 and -4, members of a large family of tight junction proteins. Toxin-induced cytolytic pore formation requires residues in the NH(2)-terminal half, whereas residues near the COOH terminus are required for binding to claudins. The claudin-binding COOH-terminal domain is not toxic and is currently under investigation as a potential drug absorption enhancer. Because claudin-4 is overexpressed on some human cancers, the toxin is also being investigated for targeting chemotherapy. Our aim was to solve the structure of the claudin-binding domain to advance its therapeutic applications. The structure of a 14-kDa fragment containing residues 194 to the native COOH terminus at position 319 was solved by x-ray diffraction to a resolution of 1.75A. The structure is a nine-strand beta sandwich with previously unappreciated similarity to the receptor-binding domains of several other toxins of spore-forming bacteria, including the collagen-binding domain of ColG from Clostridium histolyticum and the large Cry family of toxins (including Cry4Ba) of Bacillus thuringiensis. Correlations with previous studies suggest that the claudin-4 binding site is on a large surface loop between strands beta8 and beta9 or includes these strands. The sequence that was crystallized (residues 194-319) binds to purified human claudin-4 with a 1:1 stoichiometry and affinity in the submicromolar range similar to that observed for binding of native toxin to cells. Our results provide a structural framework to advance therapeutic applications of the toxin and suggest a common ancestor for several receptor-binding domains of bacterial toxins.
 
  Selected figure(s)  
 
Figure 2.
Structure of C-CPE-(194-319). The structure is a β sandwich with antiparallel orientations except for the uncommon parallel orientation of adjacent strands β1 and β3. The binding site for claudin is within the COOH-terminal 30 residues (dark blue), including strands β8 and β9 and the intervening surface loop. Mutagenesis of Tyr^306, Tyr^310, and Tyr^316 was previously shown (26) to interfere with binding to claudin.
Figure 3.
The topology of the ligand-binding domains of C-CPE-(194-319), ColG, and Cry4Ba are similar. The nine β strands (blue) of C-CPE-(194-319) are numbered from the amino end with strands 6-5-8-3-1 and 2-9-4-7 positioned on opposing sheets. Adjacent strands are antiparallel except for the uncommon parallel orientation of strands β3 and β1. This signature topology is shared by the receptor-binding domains of ColG and Cry4Ba. Surface loops are colored red. The short helix between β1 and β2 in C-CPE-(194-319) and three short β strands in Cry4Ba between β2 and β3, which are not part of the β sandwich, are removed in this presentation. Structures are oriented to optimize alignment of secondary structure elements using PRGOGRAM.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2008, 283, 268-274) copyright 2008.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21536752 D.R.Raleigh, D.M.Boe, D.Yu, C.R.Weber, A.M.Marchiando, E.M.Bradford, Y.Wang, L.Wu, E.E.Schneeberger, L.Shen, and J.R.Turner (2011).
Occludin S408 phosphorylation regulates tight junction protein interactions and barrier function.
  J Cell Biol, 193, 565-582.  
20936941 L.Shen, C.R.Weber, D.R.Raleigh, D.Yu, and J.R.Turner (2011).
Tight junction pore and leak pathways: a dynamic duo.
  Annu Rev Physiol, 73, 283-309.  
20398936 H.Kakutani, M.Kondoh, M.Fukasaka, H.Suzuki, T.Hamakubo, and K.Yagi (2010).
Mucosal vaccination using claudin-4-targeting.
  Biomaterials, 31, 5463-5471.  
19903817 J.Kimura, H.Abe, S.Kamitani, H.Toshima, A.Fukui, M.Miyake, Y.Kamata, Y.Sugita-Konishi, S.Yamamoto, and Y.Horiguchi (2010).
Clostridium perfringens enterotoxin interacts with claudins via electrostatic attraction.
  J Biol Chem, 285, 401-408.  
19447895 C.Wray, Y.Mao, J.Pan, A.Chandrasena, F.Piasta, and J.A.Frank (2009).
Claudin-4 augments alveolar epithelial barrier function and is induced in acute lung injury.
  Am J Physiol Lung Cell Mol Physiol, 297, L219-L227.  
19429681 L.Winkler, C.Gehring, A.Wenzel, S.L.Müller, C.Piehl, G.Krause, I.E.Blasig, and J.Piontek (2009).
Molecular determinants of the interaction between Clostridium perfringens enterotoxin fragments and claudin-3.
  J Biol Chem, 284, 18863-18872.  
19319969 M.K.Findley, and M.Koval (2009).
Regulation and roles for claudin-family tight junction proteins.
  IUBMB Life, 61, 431-437.  
19525389 M.Koval (2009).
Tight junctions, but not too tight: fine control of lung permeability by claudins.
  Am J Physiol Lung Cell Mol Physiol, 297, L217-L218.  
19824793 M.R.Popoff, and P.Bouvet (2009).
Clostridial toxins.
  Future Microbiol, 4, 1021-1064.  
18415116 C.Förster (2008).
Tight junctions and the modulation of barrier function in disease.
  Histochem Cell Biol, 130, 55-70.  
18782762 J.Ling, H.Liao, R.Clark, M.S.Wong, and D.D.Lo (2008).
Structural constraints for the binding of short peptides to claudin-4 revealed by surface plasmon resonance.
  J Biol Chem, 283, 30585-30595.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time.