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12  structures 10  species 3  interactions 23  sequences 1  architecture

Family: Diphtheria_R (PF01324)

Summary: Diphtheria toxin, R domain

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Diphtheria toxin Edit Wikipedia article

Diphtheria toxin, C domain
PDB 1xdt EBI.jpg
complex of diphtheria toxin and heparin-binding epidermal growth factor
Identifiers
Symbol Diphtheria_C
Pfam PF02763
Pfam clan CL0084
InterPro IPR022406
SCOP 1ddt
SUPERFAMILY 1ddt
TCDB 1.C.7
Diphtheria toxin, T domain
PDB 1xdt EBI.jpg
complex of diphtheria toxin and heparin-binding epidermal growth factor
Identifiers
Symbol Diphtheria_T
Pfam PF02764
InterPro IPR022405
SCOP 1ddt
SUPERFAMILY 1ddt
TCDB 1.C.7
Diphtheria toxin, R domain
PDB 1xdt EBI.jpg
complex of diphtheria toxin and heparin-binding epidermal growth factor
Identifiers
Symbol Diphtheria_R
Pfam PF01324
InterPro IPR022404
SCOP 1ddt
SUPERFAMILY 1ddt
TCDB 1.C.7
tox diphtheria toxin precursor
Identifiers
Organism Corynebacterium diphtheriae
Symbol tox
Entrez 2650491
RefSeq (Prot) NP_938615
UniProt Q6NK15
Other data
EC number 2.4.2.36
Chromosome genome: 0.19 - 0.19 Mb

Diphtheria toxin is an exotoxin secreted by Corynebacterium diphtheriae, the pathogen bacterium that causes diphtheria. Unusually, the toxin gene is encoded by a bacteriophage (a virus that infects bacteria).[1] The toxin causes the disease diphtheria in humans by gaining entry into the cell cytoplasm and inhibiting protein synthesis.[2]

Structure

Diphtheria toxin is a single polypeptide chain of 535 amino acids consisting of two subunits linked by disulfide bridges, known as an A-B toxin. Binding to the cell surface of the B subunit (the less stable of the two subunits) allows the A subunit (the more stable part of the protein) to penetrate the host cell.[3]

The crystal structure of the diphtheria toxin homodimer has been determined to 2.5A resolution. The structure reveals a Y-shaped molecule consisting of 3 domains. Fragment A contains the catalytic C domain, and fragment B consists of the T and R domains[4][4]

Mechanism

The diphtheria toxin has the same mechanism of action as the enzyme NAD(+)—diphthamide ADP-ribosyltransferase (EC 2.4.2.36). It catalyzes the transfer of NAD+ to a diphthamide residue in eukaryotic elongation factor-2 (eEF2), inactivating this protein. It does so by ADP-ribosylating the unusual amino acid diphthamide. In this way, it acts as a RNA translational inhibitor. The catalysed reaction is as follows:

NAD+ + peptide diphthamide \rightleftharpoons nicotinamide + peptide N-(ADP-D-ribosyl)diphthamide

The cholera toxin and exotoxin A of Pseudomonas aeruginosa uses a similar mechanism of action.

Lethal dose

Diphtheria toxin is extraordinarily potent.[3] The lethal dose for humans is about 0.1 μg of toxin per kg of bodyweight. A massive release of toxin into the body will likely cause lethal necrosis of the heart and liver.[9]

History

Diphtheria toxin was discovered in 1890 by Emil Adolf von Behring. In 1951, Freeman found that the toxin gene was not encoded on the bacterial chromosome, but by a lysogenic phage infecting all toxigenic strains.[10][11][12]

Clinical use

The drug denileukin diftitox uses diphtheria toxin as an antineoplastic agent. Resimmune™ is an immunotoxin which is in Clinical Trials in Cutaneous T cell lymphoma patients. It uses diphtheria toxin (truncated by the cell binding domain) coupled to anti-CD3ε Ab (UCHT1).

References

  1. ^ TABLE 1. Bacterial virulence properties altered by bacteriophages from Patrick L. Wagner, Matthew K. Waldor (August 2002). "Bacteriophage Control of Bacterial Virulence". Infection and Immunity 70 (8): 3985–3993. doi:10.1128/IAI.70.8.3985-3993.2002. PMC 128183. PMID 12117903. 
  2. ^ Bell CE, Eisenberg D (1996). "Crystal structure of diphtheria toxin bound to nicotinamide adenine dinucleotide". Biochemistry 35 (4): 1137–1149. doi:10.1021/bi9520848. PMID 8573568. 
  3. ^ a b Murphy JR (1996). "Corynebacterium Diphtheriae: Diphtheria Toxin Production". In Baron S et al.. Medical microbiology (4 ed.). Galveston, Texas: Univ. of Texas Medical Branch. ISBN 0-9631172-1-1. 
  4. ^ a b Choe S, Bennett MJ, Fujii G, Curmi PM, Kantardjieff KA, Collier RJ, Eisenberg D (May 1992). "The crystal structure of diphtheria toxin". Nature 357 (6375): 216–22. doi:10.1038/357216a0. PMID 1589020. 
  5. ^ a b Bell CE, Eisenberg D (January 1997). "Crystal structure of nucleotide-free diphtheria toxin". Biochemistry 36 (3): 481–8. doi:10.1021/bi962214s. PMID 9012663. 
  6. ^ a b c Bennett MJ, Eisenberg D (September 1994). "Refined structure of monomeric diphtheria toxin at 2.3 A resolution". Protein Sci. 3 (9): 1464–75. doi:10.1002/pro.5560030912. PMC 2142954. PMID 7833808. 
  7. ^ a b c Bell CE, Eisenberg D (January 1996). "Crystal structure of diphtheria toxin bound to nicotinamide adenine dinucleotide". Biochemistry 35 (4): 1137–49. doi:10.1021/bi9520848. PMID 8573568. 
  8. ^ Bennett MJ, Choe S, Eisenberg D (September 1994). "Refined structure of dimeric diphtheria toxin at 2.0 A resolution". Protein Sci. 3 (9): 1444–63. doi:10.1002/pro.5560030911. PMC 2142933. PMID 7833807. 
  9. ^ Pappenheimer A (1977). "Diphtheria toxin.". Annu Rev Biochem 46 (1): 69–94. doi:10.1146/annurev.bi.46.070177.000441. PMID 20040. 
  10. ^ Freeman VJ (June 1951). "Studies on the virulence of bacteriophage-infected strains of Corynebacterium diphtheriae". J. Bacteriol. 61 (6): 675–88. PMC 386063. PMID 14850426. 
  11. ^ Freeman VJ, Morse IU (March 1952). "Further observations on the change to virulence of bacteriophage-infected a virulent strains of Corynebacterium diphtheria". J. Bacteriol. 63 (3): 407–14. PMC 169283. PMID 14927573. 
  12. ^ Diphtheria from Todar's Online Textbook of Bacteriology, Kenneth Todar 2009. Accessed 08 September 2010.

External links

This article incorporates text from the public domain Pfam and InterPro IPR022406

This article incorporates text from the public domain Pfam and InterPro IPR022405

This article incorporates text from the public domain Pfam and InterPro IPR022404

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Diphtheria toxin, R domain Provide feedback

C-terminal receptor binding (R) domain - binds to cell surface receptor, permitting the toxin to enter the cell by receptor mediated endocytosis.

Literature references

  1. Bennett MJ, Eisenberg D; , Protein Sci 1994;3:1464-1475.: Refined structure of monomeric diphtheria toxin at 2.3 A resolution. PUBMED:7833808 EPMC:7833808

  2. Bell CE, Eisenberg D; , Biochemistry 1996;35:1137-1149.: Crystal structure of diphtheria toxin bound to nicotinamide adenine dinucleotide. PUBMED:8573568 EPMC:8573568


Internal database links

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR022404

This entry represents the C-terminal receptor-binding domain, also known as the R domain. This domain has a beta-sandwich fold consisiting of nine strands in two sheet with greek-key topology; it is a subclass of immunoglobin-like fold [PUBMED:9012663]. The R domain binds to cell surface receptor, permitting the toxin to enter the cell by receptor mediated endocytosis [PUBMED:7833808, PUBMED:8573568].

Diphtheria toxin (EC) is a 58 kDa protein secreted by lysogenic strains of Corynebacterium diphtheriae. The toxin causes the disease diphtheria in humans by gaining entry into the cell cytoplasm and inhibiting protein synthesis [PUBMED:8573568]. The mechanism of inhibition involves transfer of the ADP-ribose group of NAD to elongation factor-2 (EF-2), rendering EF-2 inactive. The catalysed reaction is as follows: NAD+ + peptide diphthamide = nicotinamide + peptide N-(ADP-D-ribosyl)diphthamide

The crystal structure of the diphtheria toxin homodimer has been determined to 2.5A resolution [PUBMED:1589020]. The structure reveals a Y-shaped molecule of 3 domains, a catalytic domain (fragment A), whose fold is of the alpha + beta type; a transmembrane (TM) domain, which consists of 9 alpha-helices, 2 pairs of which may participate in pH-triggered membrane insertion and translocation; and a receptor-binding domain, which forms a flattened beta-barrel with a jelly-roll-like topology [PUBMED:1589020]. The TM- and receptor binding-domains together constitute fragment B.

Domain organisation

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Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Sarah Teichmann
Previous IDs: Diphtheria_tox;
Type: Domain
Author: Finn RD, Bateman A, Griffiths-Jones SR
Number in seed: 3
Number in full: 23
Average length of the domain: 138.70 aa
Average identity of full alignment: 95 %
Average coverage of the sequence by the domain: 26.57 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 25.0 25.0
Trusted cut-off 27.8 81.2
Noise cut-off 19.6 18.7
Model length: 154
Family (HMM) version: 14
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Species distribution

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Interactions

There are 3 interactions for this family. More...

Diphtheria_R Diphtheria_T Diphtheria_C

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Diphtheria_R domain has been found. There are 12 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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