PDBsum entry 1mdt

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Toxin PDB id
Protein chains
523 a.a.
APU ×2
Waters ×396
PDB id:
Name: Toxin
Title: The refined structure of monomeric diphtheria toxin at 2.3 angstroms resolution
Structure: Diphtheria toxin. Chain: a, b. Engineered: yes
Source: Corynephage beta. Organism_taxid: 10703
2.30Å     R-factor:   0.207    
Authors: M.J.Bennett,D.Eisenberg
Key ref: M.J.Bennett and D.Eisenberg (1994). Refined structure of monomeric diphtheria toxin at 2.3 A resolution. Protein Sci, 3, 1464-1475. PubMed id: 7833808 DOI: 10.1002/pro.5560030912
21-Mar-94     Release date:   31-Jul-94    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P00588  (DTX_CORBE) -  Diphtheria toxin
567 a.a.
523 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.  - NAD(+)--diphthamide ADP-ribosyltransferase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: NAD+ + diphthamide-[translation elongation factor 2] = nicotinamide + N-(ADP-D-ribosyl)diphthamide-[translation elongation factor 2]
+ diphthamide-[translation elongation factor 2]
= nicotinamide
+ N-(ADP-D-ribosyl)diphthamide-[translation elongation factor 2]
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   1 term 
  Biological process     metabolic process   2 terms 
  Biochemical function     transferase activity     3 terms  


    Added reference    
DOI no: 10.1002/pro.5560030912 Protein Sci 3:1464-1475 (1994)
PubMed id: 7833808  
Refined structure of monomeric diphtheria toxin at 2.3 A resolution.
M.J.Bennett, D.Eisenberg.
The structure of toxic monomeric diphtheria toxin (DT) was determined at 2.3 A resolution by molecular replacement based on the domain structures in dimeric DT and refined to an R factor of 20.7%. The model consists of 2 monomers in the asymmetric unit (1,046 amino acid residues), including 2 bound adenylyl 3'-5' uridine 3' monophosphate molecules and 396 water molecules. The structures of the 3 domains are virtually identical in monomeric and dimeric DT; however, monomeric DT is compact and globular as compared to the "open" monomer within dimeric DT (Bennett MJ, Choe S, Eisenberg D, 1994b, Protein Sci 3:0000-0000). Detailed differences between monomeric and dimeric DT are described, particularly (1) changes in main-chain conformations of 8 residues acting as a hinge to "open" or "close" the receptor-binding (R) domain, and (2) a possible receptor-docking site, a beta-hairpin loop protruding from the R domain containing residues that bind the cell-surface DT receptor. Based on the monomeric and dimeric DT crystal structures we have determined and the solution studies of others, we present a 5-step structure-based mechanism of intoxication: (1) proteolysis of a disulfide-linked surface loop (residues 186-201) between the catalytic (C) and transmembrane (T) domains; (2) binding of a beta-hairpin loop protruding from the R domain to the DT receptor, leading to receptor-mediated endocytosis; (3) low pH-triggered open monomer formation and exposure of apolar surfaces in the T domain, which insert into the endosomal membrane; (4) translocation of the C domain into the cytosol; and (5) catalysis by the C domain of ADP-ribosylation of elongation factor 2.

Literature references that cite this PDB file's key reference

  PubMed id Reference
20814829 S.Potala, and R.S.Verma (2011).
Targeting head and neck squamous cell carcinoma using a novel fusion toxin-diphtheria toxin/HN-1.
  Mol Biol Rep, 38, 1389-1397.  
20564044 I.Nakase, S.Kobayashi, and S.Futaki (2010).
Endosome-disruptive peptides for improving cytosolic delivery of bioactive macromolecules.
  Biopolymers, 94, 763-770.  
20050921 P.Man, C.Montagner, H.Vitrac, D.Kavan, S.Pichard, D.Gillet, E.Forest, and V.Forge (2010).
Accessibility changes within diphtheria toxin T domain when in the functional molten globule state, as determined using hydrogen/deuterium exchange measurements.
  FEBS J, 277, 653-662.  
20091872 R.P.Nagarkar, R.A.Hule, D.J.Pochan, and J.P.Schneider (2010).
Domain swapping in materials design.
  Biopolymers, 94, 141-155.  
20084469 S.Potala, and R.S.Verma (2010).
A novel fusion protein diphtheria toxin-stem cell factor (DT-SCF)-purification and characterization.
  Appl Biochem Biotechnol, 162, 1258-1269.  
19588969 A.Kyrychenko, Y.O.Posokhov, M.V.Rodnin, and A.S.Ladokhin (2009).
Kinetic intermediate reveals staggered pH-dependent transitions along the membrane insertion pathway of the diphtheria toxin T-domain.
  Biochemistry, 48, 7584-7594.  
19344187 R.J.Kreitman (2009).
Recombinant immunotoxins containing truncated bacterial toxins for the treatment of hematologic malignancies.
  BioDrugs, 23, 1.  
19137579 S.Rodziewicz-Motowidło, J.Iwaszkiewicz, R.Sosnowska, P.Czaplewska, E.Sobolewski, A.Szymańska, K.Stachowiak, and A.Liwo (2009).
The role of the Val57 amino-acid residue in the hinge loop of the human cystatin C. Conformational studies of the beta2-L1-beta3 segments of wild-type human cystatin C and its mutants.
  Biopolymers, 91, 373-383.  
18055530 M.S.Kent, H.Yim, J.K.Murton, S.Satija, J.Majewski, and I.Kuzmenko (2008).
Oligomerization of membrane-bound diphtheria toxin (CRM197) facilitates a transition to the open form and deep insertion.
  Biophys J, 94, 2115-2127.  
18678276 S.Potala, S.K.Sahoo, and R.S.Verma (2008).
Targeted therapy of cancer using diphtheria toxin-derived immunotoxins.
  Drug Discov Today, 13, 807-815.  
17025272 R.J.Kreitman (2006).
Immunotoxins for targeted cancer therapy.
  AAPS J, 8, E532-E551.  
16154093 D.B.Huang, D.Vu, and G.Ghosh (2005).
NF-kappaB RelB forms an intertwined homodimer.
  Structure, 13, 1365-1373.
PDB codes: 1zk9 1zka
15184133 J.H.Woo, Y.Y.Liu, S.Stavrou, and D.M.Neville (2004).
Increasing secretion of a bivalent anti-T-cell immunotoxin by Pichia pastoris.
  Appl Environ Microbiol, 70, 3370-3376.  
15189881 S.Kundu, and R.L.Jernigan (2004).
Molecular mechanism of domain swapping in proteins: an analysis of slower motions.
  Biophys J, 86, 3846-3854.  
12414710 H.H.Gan, R.A.Perlow, S.Roy, J.Ko, M.Wu, J.Huang, S.Yan, A.Nicoletta, J.Vafai, D.Sun, L.Wang, J.E.Noah, S.Pasquali, and T.Schlick (2002).
Analysis of protein sequence/structure similarity relationships.
  Biophys J, 83, 2781-2791.  
12021428 Y.Liu, and D.Eisenberg (2002).
3D domain swapping: as domains continue to swap.
  Protein Sci, 11, 1285-1299.  
  11696606 M.Gordon, and A.Finkelstein (2001).
The number of subunits comprising the channel formed by the T domain of diphtheria toxin.
  J Gen Physiol, 118, 471-480.  
11123917 B.Steere, and D.Eisenberg (2000).
Characterization of high-order diphtheria toxin oligomers.
  Biochemistry, 39, 15901-15909.  
10944393 H.Ponstingl, K.Henrick, and J.M.Thornton (2000).
Discriminating between homodimeric and monomeric proteins in the crystalline state.
  Proteins, 41, 47-57.  
10657208 R.K.Holmes (2000).
Biology and molecular epidemiology of diphtheria toxin and the tox gene.
  J Infect Dis, 181, S156-S167.  
  10496871 C.Fromen-Romano, P.Drevet, A.Robert, A.Ménez, and M.Léonetti (1999).
Recombinant Staphylococcus strains as live vectors for the induction of neutralizing anti-diphtheria toxin antisera.
  Infect Immun, 67, 5007-5011.  
10411898 K.J.Oh, L.Senzel, R.J.Collier, and A.Finkelstein (1999).
Translocation of the catalytic domain of diphtheria toxin across planar phospholipid bilayers by its own T domain.
  Proc Natl Acad Sci U S A, 96, 8467-8470.  
9888806 P.Quertenmont, C.Wolff, R.Wattiez, P.Vander Borght, P.Falmagne, J.M.Ruysschaert, and V.Cabiaux (1999).
Structure and topology of diphtheria toxin R domain in lipid membranes.
  Biochemistry, 38, 660-666.  
10837618 I.Pastan, and R.J.Kreitman (1998).
Immunotoxins for targeted cancer therapy.
  Adv Drug Deliv Rev, 31, 53-88.  
  9453589 K.Lobeck, P.Drevet, M.Léonetti, C.Fromen-Romano, F.Ducancel, E.Lajeunesse, C.Lemaire, and A.Ménez (1998).
Towards a recombinant vaccine against diphtheria toxin.
  Infect Immun, 66, 418-423.  
  9725891 L.Senzel, P.D.Huynh, K.S.Jakes, R.J.Collier, and A.Finkelstein (1998).
The diphtheria toxin channel-forming T domain translocates its own NH2-terminal region across planar bilayers.
  J Gen Physiol, 112, 317-324.  
9693002 M.Coles, W.Bicknell, A.A.Watson, D.P.Fairlie, and D.J.Craik (1998).
Solution structure of amyloid beta-peptide(1-40) in a water-micelle environment. Is the membrane-spanning domain where we think it is?
  Biochemistry, 37, 11064-11077.
PDB code: 1ba4
15992040 R.J.Kreitman (1998).
Recombinant toxins in haematologic malignancies and solid tumours.
  Expert Opin Investig Drugs, 7, 1405-1427.  
9922159 S.E.Malenbaum, R.J.Collier, and E.London (1998).
Membrane topography of the T domain of diphtheria toxin probed with single tryptophan mutants.
  Biochemistry, 37, 17915-17922.  
9012663 C.E.Bell, and D.Eisenberg (1997).
Crystal structure of nucleotide-free diphtheria toxin.
  Biochemistry, 36, 481-488.
PDB code: 1sgk
9208920 D.T.Crane, B.Bolgiano, and C.Jones (1997).
Comparison of the diphtheria mutant toxin, CRM197, with a Haemophilus influenzae type-b polysaccharide-CRM197 conjugate by optical spectroscopy.
  Eur J Biochem, 246, 320-327.  
  8993861 G.Funke, A.von Graevenitz, J.E.Clarridge, and K.A.Bernard (1997).
Clinical microbiology of coryneform bacteria.
  Clin Microbiol Rev, 10, 125-159.  
9659904 G.V.Louie, W.Yang, M.E.Bowman, and S.Choe (1997).
Crystal structure of the complex of diphtheria toxin with an extracellular fragment of its receptor.
  Mol Cell, 1, 67-78.
PDB code: 1xdt
  9276751 P.D.Huynh, C.Cui, H.Zhan, K.J.Oh, R.J.Collier, and A.Finkelstein (1997).
Probing the structure of the diphtheria toxin channel. Reactivity in planar lipid bilayer membranes of cysteine-substituted mutant channels with methanethiosulfonate derivatives.
  J Gen Physiol, 110, 229-242.  
8573568 C.E.Bell, and D.Eisenberg (1996).
Crystal structure of diphtheria toxin bound to nicotinamide adenine dinucleotide.
  Biochemistry, 35, 1137-1149.
PDB code: 1tox
8805549 F.van den Akker, S.Sarfaty, E.M.Twiddy, T.D.Connell, R.K.Holmes, and W.G.Hol (1996).
Crystal structure of a new heat-labile enterotoxin, LT-IIb.
  Structure, 4, 665-678.
PDB code: 1tii
7648317 E.A.Merritt, and W.G.Hol (1995).
AB5 toxins.
  Curr Opin Struct Biol, 5, 165-171.  
  8580836 M.J.Bennett, M.P.Schlunegger, and D.Eisenberg (1995).
3D domain swapping: a mechanism for oligomer assembly.
  Protein Sci, 4, 2455-2468.  
8566002 R.Raju, D.Navaneetham, D.Okita, B.Diethelm-Okita, D.McCormick, and B.M.Conti-Fine (1995).
Epitopes for human CD4+ cells on diphtheria toxin: structural features of sequence segments forming epitopes recognized by most subjects.
  Eur J Immunol, 25, 3207-3214.  
  7833808 M.J.Bennett, and D.Eisenberg (1994).
Refined structure of monomeric diphtheria toxin at 2.3 A resolution.
  Protein Sci, 3, 1464-1475.
PDB code: 1mdt
  7833807 M.J.Bennett, S.Choe, and D.Eisenberg (1994).
Refined structure of dimeric diphtheria toxin at 2.0 A resolution.
  Protein Sci, 3, 1444-1463.
PDB code: 1ddt
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. Where a reference describes a PDB structure, the PDB codes are shown on the right.