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16  structures 12  species 3  interactions 12  sequences 5  architectures

Family: Diphtheria_T (PF02764)

Summary: Diphtheria toxin, T domain

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This is the Wikipedia entry entitled "Diphtheria toxin". More...

Diphtheria toxin Edit Wikipedia article

tox diphtheria toxin precursor
PDB 1xdt EBI.jpg
complex of diphtheria toxin and heparin-binding epidermal growth factor
OrganismCorynebacterium diphtheriae
RefSeq (Prot)NP_938615
Other data
EC number2.4.2.36
Chromosomegenome: 0.19 - 0.19 Mb
Diphtheria toxin, C domain
Pfam clanCL0084
Diphtheria toxin, T domain
Diphtheria toxin, R domain

Diphtheria toxin is an exotoxin secreted by Corynebacterium, the pathogenic bacterium that causes diphtheria. The toxin gene is encoded by a prophage (a virus that has inserted itself into the genome of the host bacterium).[1] The toxin causes the disease in humans by gaining entry into the cell cytoplasm and inhibiting protein synthesis.[2]


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 2.5 Ã…ngstrom resolution. The structure reveals a Y-shaped molecule consisting of three domains. Fragment A contains the catalytic C domain, and fragment B consists of the T and R domains:[4][4]


  1. Processing
    1. The leader region is cleaved during secretion.
    2. Proteolytic nicking separates A and B subunits, which remain joined by disulfide bonds until they reach the cytosol.
  2. The toxin binds to heparin-binding epidermal growth factor precursor (HB-EGF).
  3. The complex undergoes endocytosis by the host cell.
  4. Acidification inside the endosome induces translocation of the A subunit into the cytosol.
    1. Disulfide bonds are broken.
    2. The B subunit remains in the endosome as a pore.
  5. A subunit ADP-ribosylates host eEF-2. eEF-2 is required for protein synthesis; when it is inactivated, the host cannot make protein and thus dies.

The diphtheria toxin has the same mechanism of action as the enzyme NAD(+)—diphthamide ADP-ribosyltransferase (EC It catalyzes the transfer of NAD+ to a diphthamide residue in eEF-2, 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 nicotinamide + peptide N-(ADP-D-ribosyl)diphthamide.

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

Lethal dose and effects

Diphtheria toxin is extraordinarily potent.[3] The lethal dose for humans is about 0.1 μg of toxin per kg of body weight. Death occurs through necrosis of the heart and liver.[9] Diphtheria toxin has also been associated with the development of myocarditis. Myocarditis secondary to diphtheria toxin is considered one of the biggest risks to unimmunized children.


Diphtheria toxin was discovered in 1888 by Émile Roux and Alexandre Yersin. In 1890, Emil Adolf von Behring developed an anti-toxin based on the blood of horses immunized with attenuated bacteria.[10] In 1951, Freeman found that the toxin gene was not encoded on the bacterial chromosome, but by a lysogenic phage infecting all toxigenic strains.[11][12][13]

Clinical use

The drug denileukin diftitox uses diphtheria toxin as an antineoplastic agent.

Resimmune is an immunotoxin that is in clinical trials in Cutaneous T cell lymphoma patients. It uses diphtheria toxin (truncated by the cell binding domain) coupled to an antibody to CD3ε (UCHT1).{[14]


Similar to other A-B toxins, diphtheria toxin is adept at transporting exogenous proteins across mammalian cell membranes, which are usually impermeable to large proteins. This unique ability can be repurposed to deliver therapeutic proteins, instead of the catalytic domain of the toxin.[15][16]


  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. (eds.). Medical microbiology (4th ed.). Galveston, Texas: Univ. of Texas Medical Branch. ISBN 978-0-9631172-1-2. PMID 21413281.
  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. CiteSeerX 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/ PMID 20040.
  10. ^ Enke, U (2015): 125 Jahre Diphtherieheilserum, Dtsch Arztebl 2015; 112(49): A-2088
  11. ^ 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.
  12. ^ Freeman VJ, Morse IU (March 1952). "Further observations on the change to virulence of bacteriophage-infected avirulent strains of Corynebacterium diphtheria". J. Bacteriol. 63 (3): 407–14. PMC 169283. PMID 14927573.
  13. ^ Diphtheria from Todar's Online Textbook of Bacteriology, Kenneth Todar 2009. Accessed 08 September 2010.
  14. ^ Woo, JH; Lee YJ; Neville DM; Frankel AE. (2010). "Pharmacology of anti-CD3 diphtheria immunotoxin in CD3 positive T-cell lymphoma trials". Methods Mol. Biol. 651 (651): 157–75. doi:10.1007/978-1-60761-786-0_10. PMID 20686966.
  15. ^ Auger A, Park M, Nitschke F, Minassian LM, Beilhartz GL, Minassian BA, Melnyk RA (August 2015). "Efficient Delivery of Structurally Diverse Protein Cargo into Mammalian Cells by a Bacterial Toxin". Molecular Pharmaceutics. 12 (8): 2962–71. doi:10.1021/acs.molpharmaceut.5b00233. PMID 26103531.
  16. ^ Beilhartz GL, Sugiman-Marangos SN, Melnyk RA (October 2017). "Repurposing bacterial toxins for intracellular delivery of therapeutic proteins". Biochemical Pharmacology. 142: 13–20. doi:10.1016/j.bcp.2017.04.009. PMID 28408344.

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, T domain Provide feedback

Central domain of diphtheria toxin is the translocation (T) domain. pH induced conformational change in this domain triggers insertion into the endosomal membrane and facilitates the transfer of the catalytic domain into the cytoplasm.

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

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR022405

Diphtheria toxin (EC) is a 58kDa 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.

This entry represents the translocation domain (also known as the T domain) found as the central domain in the Diphtheria toxin protein. The T domain has a multi-helical globin-like fold with two additional helices at N-termini, but which has no counterpart to the first globin helix. This domain is thought to unfold in the membrane [PUBMED:7833807]. pH-induced conformational change in the T domain triggers insertion into the endosomal membrane and facilitates the transfer of the catalytic domain into the cytoplasm [PUBMED:7833808, PUBMED:8573568].

Domain organisation

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Seed source: Sarah Teichmann
Previous IDs: none
Type: Domain
Sequence Ontology: SO:0000417
Author: Finn RD , Bateman A , Griffiths-Jones SR
Number in seed: 1
Number in full: 12
Average length of the domain: 162.30 aa
Average identity of full alignment: 44 %
Average coverage of the sequence by the domain: 20.59 %

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HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 47079205 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 25.0 25.0
Trusted cut-off 25.5 27.4
Noise cut-off 24.9 24.6
Model length: 180
Family (HMM) version: 15
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Species distribution

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

Diphtheria_C Diphtheria_R Diphtheria_R


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_T domain has been found. There are 16 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 sequence.

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