DTX_CORBE
ID DTX_CORBE Reviewed; 567 AA.
AC P00588;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-1991, sequence version 2.
DT 03-AUG-2022, entry version 133.
DE RecName: Full=Diphtheria toxin;
DE Short=DT;
DE AltName: Full=NAD(+)--diphthamide ADP-ribosyltransferase;
DE EC=2.4.2.36;
DE Contains:
DE RecName: Full=Diphtheria toxin fragment A;
DE Contains:
DE RecName: Full=Diphtheria toxin fragment B;
DE Flags: Precursor;
OS Corynephage beta.
OC Viruses; Duplodnaviria; Heunggongvirae; Uroviricota; Caudoviricetes;
OC Caudovirales; Siphoviridae; Lambdavirus; unclassified Lambdavirus.
OX NCBI_TaxID=10703;
OH NCBI_TaxID=1717; Corynebacterium diphtheriae.
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=6316330; DOI=10.1073/pnas.80.22.6853;
RA Greenfield L., Bjorn M.J., Horn G., Fong D., Buck G.A., Collier R.J.,
RA Kaplan D.A.;
RT "Nucleotide sequence of the structural gene for diphtheria toxin carried by
RT corynebacteriophage beta.";
RL Proc. Natl. Acad. Sci. U.S.A. 80:6853-6857(1983).
RN [2]
RP PROTEIN SEQUENCE OF 33-225.
RX PubMed=221484; DOI=10.1016/s0021-9258(18)50488-9;
RA Delange R.J., Williams L.C., Drazin R.E., Collier R.J.;
RT "The amino acid sequence of fragment A, an enzymically active fragment of
RT diphtheria toxin. III. The chymotryptic peptides, the peptides derived by
RT cleavage at tryptophan residues, and the complete sequence of the
RT protein.";
RL J. Biol. Chem. 254:5838-5842(1979).
RN [3]
RP ACTIVE SITE TRP-185.
RX PubMed=849463; DOI=10.1016/0005-2795(77)90064-2;
RA Michel A., Dirkx J.;
RT "Occurrence of tryptophan in the enzymically active site of diphtheria
RT toxin fragment A.";
RL Biochim. Biophys. Acta 491:286-295(1977).
RN [4]
RP ACTIVE SITE TYR-97.
RX PubMed=1990001; DOI=10.1016/s0021-9258(18)52271-7;
RA Papini E., Santucci A., Schiavo G., Domenighini M., Neri P., Rappuoli R.,
RA Montecucco C.;
RT "Tyrosine 65 is photolabeled by 8-azidoadenine and 8-azidoadenosine at the
RT NAD binding site of diphtheria toxin.";
RL J. Biol. Chem. 266:2494-2498(1991).
RN [5]
RP PROTEOLYTIC CLEAVAGE.
RX PubMed=8253774; DOI=10.1016/s0021-9258(19)74337-3;
RA Tsuneoka M., Nakayama K., Hatsuzawa K., Komada M., Kitamura N., Mekada E.;
RT "Evidence for involvement of furin in cleavage and activation of diphtheria
RT toxin.";
RL J. Biol. Chem. 268:26461-26465(1993).
RN [6]
RP FUNCTION AS AN ADP-RIBOSYLTRANSFERASE.
RX PubMed=18276581; DOI=10.1074/jbc.m710008200;
RA Jorgensen R., Purdy A.E., Fieldhouse R.J., Kimber M.S., Bartlett D.H.,
RA Merrill A.R.;
RT "Cholix toxin, a novel ADP-ribosylating factor from Vibrio cholerae.";
RL J. Biol. Chem. 283:10671-10678(2008).
RN [7]
RP FUNCTION AS A TOXIN, FUNCTION AS AN ADP-RIBOSYLTRANSFERASE, ACTIVITY
RP REGULATION, EXPRESSION IN YEAST, AND MUTAGENESIS OF GLU-180.
RX PubMed=19793133; DOI=10.1111/j.1574-6968.2009.01777.x;
RA Turgeon Z., White D., Jorgensen R., Visschedyk D., Fieldhouse R.J.,
RA Mangroo D., Merrill A.R.;
RT "Yeast as a tool for characterizing mono-ADP-ribosyltransferase toxins.";
RL FEMS Microbiol. Lett. 300:97-106(2009).
RN [8]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS).
RX PubMed=1589020; DOI=10.1038/357216a0;
RA Choe S., Bennett M.J., Fujii G., Curmi P.M.G., Kantardjieff K.A.,
RA Collier R.J., Eisenberg D.;
RT "The crystal structure of diphtheria toxin.";
RL Nature 357:216-222(1992).
RN [9]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS).
RX PubMed=8573568; DOI=10.1021/bi9520848;
RA Bell C.E., Eisenberg D.;
RT "Crystal structure of diphtheria toxin bound to nicotinamide adenine
RT dinucleotide.";
RL Biochemistry 35:1137-1149(1996).
RN [10]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS).
RX PubMed=9012663; DOI=10.1021/bi962214s;
RA Bell C.E., Eisenberg D.;
RT "Crystal structure of nucleotide-free diphtheria toxin.";
RL Biochemistry 36:481-488(1997).
RN [11]
RP X-RAY CRYSTALLOGRAPHY (2.65 ANGSTROMS) OF COMPLEX WITH RECEPTOR.
RX PubMed=9659904; DOI=10.1016/s1097-2765(00)80008-8;
RA Louie G.V., Yang W., Bowman M.E., Choe S.;
RT "Crystal structure of the complex of diphtheria toxin with an extracellular
RT fragment of its receptor.";
RL Mol. Cell 1:67-78(1997).
CC -!- FUNCTION: Diphtheria toxin, produced by a phage infecting
CC Corynebacterium diphtheriae, is a proenzyme that, after activation,
CC catalyzes the covalent attachment of the ADP ribose moiety of NAD to
CC eukaryotic elongation factor 2 (eEF-2). Fragment A is the catalytic
CC portion responsible for enzymatic ADP-ribosylation of elongation factor
CC 2, while fragment B is responsible for binding of toxin to cell
CC receptors and entry of fragment A. {ECO:0000269|PubMed:18276581,
CC ECO:0000269|PubMed:19793133}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=diphthamide-[translation elongation factor 2] + NAD(+) = H(+)
CC + N-(ADP-D-ribosyl)diphthamide-[translation elongation factor 2] +
CC nicotinamide; Xref=Rhea:RHEA:11820, Rhea:RHEA-COMP:10174, Rhea:RHEA-
CC COMP:10175, ChEBI:CHEBI:15378, ChEBI:CHEBI:16692, ChEBI:CHEBI:17154,
CC ChEBI:CHEBI:57540, ChEBI:CHEBI:82697; EC=2.4.2.36;
CC -!- ACTIVITY REGULATION: Partially inhibited by 1,8-naphthalimide (NAP).
CC {ECO:0000269|PubMed:19793133}.
CC -!- SUBUNIT: Homodimer.
CC -!- INTERACTION:
CC P00588; P00588: -; NbExp=2; IntAct=EBI-15975409, EBI-15975409;
CC -!- PTM: Proteolytic activation by host furin cleaves the protein in two
CC parts, Diphtheria toxin fragment A and Diphtheria toxin fragment B;
CC which remain associated via a disulfide bond.
CC {ECO:0000269|PubMed:8253774}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA32182.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR EMBL; K01722; AAA32182.1; ALT_INIT; Genomic_DNA.
DR EMBL; X00703; CAA25302.1; -; Genomic_DNA.
DR PDB; 1DDT; X-ray; 2.00 A; A=33-567.
DR PDB; 1DTP; X-ray; 2.50 A; A=33-222.
DR PDB; 1F0L; X-ray; 1.55 A; A/B=33-567.
DR PDB; 1MDT; X-ray; 2.30 A; A/B=33-567.
DR PDB; 1SGK; X-ray; 2.30 A; A=33-567.
DR PDB; 1TOX; X-ray; 2.30 A; A/B=33-567.
DR PDB; 1XDT; X-ray; 2.65 A; T=33-567.
DR PDB; 4AE0; X-ray; 2.00 A; A=33-567.
DR PDB; 4AE1; X-ray; 2.08 A; A/B=33-567.
DR PDBsum; 1DDT; -.
DR PDBsum; 1DTP; -.
DR PDBsum; 1F0L; -.
DR PDBsum; 1MDT; -.
DR PDBsum; 1SGK; -.
DR PDBsum; 1TOX; -.
DR PDBsum; 1XDT; -.
DR PDBsum; 4AE0; -.
DR PDBsum; 4AE1; -.
DR BMRB; P00588; -.
DR SMR; P00588; -.
DR DIP; DIP-60031N; -.
DR BioCyc; MetaCyc:MON-15583; -.
DR BRENDA; 3.2.2.22; 14080.
DR Reactome; R-HSA-5336415; Uptake and function of diphtheria toxin.
DR EvolutionaryTrace; P00588; -.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IEA:InterPro.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0047286; F:NAD+-diphthamide ADP-ribosyltransferase activity; EXP:Reactome.
DR GO; GO:0008320; F:protein transmembrane transporter activity; TAS:Reactome.
DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
DR Gene3D; 2.60.40.700; -; 1.
DR InterPro; IPR036799; Diphtheria_tox_rcpt-bd_dom_sf.
DR InterPro; IPR036801; Diphtheria_tox_transloc_sf.
DR InterPro; IPR000512; Diphtheria_toxin.
DR InterPro; IPR022406; Diphtheria_toxin_catalytic_dom.
DR InterPro; IPR022404; Diphtheria_toxin_rcpt-bd_dom.
DR InterPro; IPR022405; Diphtheria_toxin_translocation.
DR Pfam; PF02763; Diphtheria_C; 1.
DR Pfam; PF01324; Diphtheria_R; 1.
DR Pfam; PF02764; Diphtheria_T; 1.
DR PIRSF; PIRSF000490; Diphtheria_toxin; 1.
DR PRINTS; PR00769; DPTHRIATOXIN.
DR SUPFAM; SSF49380; SSF49380; 1.
DR SUPFAM; SSF56845; SSF56845; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cleavage on pair of basic residues;
KW Direct protein sequencing; Disulfide bond; Glycosyltransferase; NAD;
KW Nucleotidyltransferase; Signal; Toxin; Transferase.
FT SIGNAL 1..32
FT /evidence="ECO:0000269|PubMed:221484"
FT CHAIN 33..225
FT /note="Diphtheria toxin fragment A"
FT /id="PRO_0000019345"
FT CHAIN 226..567
FT /note="Diphtheria toxin fragment B"
FT /id="PRO_0000019346"
FT ACT_SITE 180
FT BINDING 53
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT BINDING 97
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT SITE 185
FT /note="Modification inactivates enzyme"
FT SITE 225..226
FT /note="Cleavage; by furin"
FT /evidence="ECO:0000269|PubMed:8253774"
FT DISULFID 218..233
FT DISULFID 493..503
FT MUTAGEN 180
FT /note="E->A: Loss of toxicity."
FT /evidence="ECO:0000269|PubMed:19793133"
FT CONFLICT 178..180
FT /note="SVE -> VES (in Ref. 2; AA sequence)"
FT /evidence="ECO:0000305"
FT HELIX 34..37
FT /evidence="ECO:0007829|PDB:1F0L"
FT HELIX 40..42
FT /evidence="ECO:0007829|PDB:1F0L"
FT STRAND 44..47
FT /evidence="ECO:0007829|PDB:1F0L"
FT STRAND 50..55
FT /evidence="ECO:0007829|PDB:1F0L"
FT TURN 57..61
FT /evidence="ECO:0007829|PDB:1MDT"
FT HELIX 62..65
FT /evidence="ECO:0007829|PDB:1F0L"
FT STRAND 71..73
FT /evidence="ECO:0007829|PDB:1F0L"
FT HELIX 80..82
FT /evidence="ECO:0007829|PDB:1F0L"
FT STRAND 84..89
FT /evidence="ECO:0007829|PDB:1F0L"
FT HELIX 91..95
FT /evidence="ECO:0007829|PDB:1F0L"
FT STRAND 101..103
FT /evidence="ECO:0007829|PDB:1XDT"
FT TURN 104..106
FT /evidence="ECO:0007829|PDB:1F0L"
FT STRAND 111..116
FT /evidence="ECO:0007829|PDB:1F0L"
FT STRAND 118..127
FT /evidence="ECO:0007829|PDB:1F0L"
FT HELIX 131..137
FT /evidence="ECO:0007829|PDB:1F0L"
FT STRAND 142..144
FT /evidence="ECO:0007829|PDB:4AE0"
FT HELIX 146..150
FT /evidence="ECO:0007829|PDB:1F0L"
FT HELIX 153..159
FT /evidence="ECO:0007829|PDB:1F0L"
FT STRAND 160..162
FT /evidence="ECO:0007829|PDB:1DTP"
FT STRAND 164..171
FT /evidence="ECO:0007829|PDB:1F0L"
FT STRAND 179..183
FT /evidence="ECO:0007829|PDB:1F0L"
FT HELIX 187..190
FT /evidence="ECO:0007829|PDB:1F0L"
FT STRAND 192..198
FT /evidence="ECO:0007829|PDB:1F0L"
FT HELIX 199..202
FT /evidence="ECO:0007829|PDB:1F0L"
FT HELIX 208..215
FT /evidence="ECO:0007829|PDB:1F0L"
FT HELIX 216..218
FT /evidence="ECO:0007829|PDB:1F0L"
FT HELIX 238..253
FT /evidence="ECO:0007829|PDB:1F0L"
FT HELIX 256..263
FT /evidence="ECO:0007829|PDB:1F0L"
FT HELIX 272..286
FT /evidence="ECO:0007829|PDB:1F0L"
FT HELIX 290..292
FT /evidence="ECO:0007829|PDB:1F0L"
FT HELIX 293..299
FT /evidence="ECO:0007829|PDB:1F0L"
FT HELIX 303..305
FT /evidence="ECO:0007829|PDB:1F0L"
FT HELIX 307..320
FT /evidence="ECO:0007829|PDB:1F0L"
FT HELIX 323..326
FT /evidence="ECO:0007829|PDB:1F0L"
FT HELIX 329..336
FT /evidence="ECO:0007829|PDB:1F0L"
FT HELIX 342..346
FT /evidence="ECO:0007829|PDB:1F0L"
FT HELIX 358..379
FT /evidence="ECO:0007829|PDB:1F0L"
FT TURN 387..390
FT /evidence="ECO:0007829|PDB:1F0L"
FT HELIX 391..407
FT /evidence="ECO:0007829|PDB:1F0L"
FT STRAND 421..423
FT /evidence="ECO:0007829|PDB:1F0L"
FT STRAND 426..432
FT /evidence="ECO:0007829|PDB:1F0L"
FT HELIX 433..436
FT /evidence="ECO:0007829|PDB:1F0L"
FT STRAND 437..439
FT /evidence="ECO:0007829|PDB:1F0L"
FT STRAND 444..457
FT /evidence="ECO:0007829|PDB:1F0L"
FT STRAND 459..461
FT /evidence="ECO:0007829|PDB:1F0L"
FT STRAND 463..467
FT /evidence="ECO:0007829|PDB:1F0L"
FT TURN 470..472
FT /evidence="ECO:0007829|PDB:1F0L"
FT STRAND 473..475
FT /evidence="ECO:0007829|PDB:1F0L"
FT TURN 477..479
FT /evidence="ECO:0007829|PDB:1F0L"
FT STRAND 481..484
FT /evidence="ECO:0007829|PDB:1F0L"
FT STRAND 487..489
FT /evidence="ECO:0007829|PDB:1F0L"
FT STRAND 491..496
FT /evidence="ECO:0007829|PDB:1F0L"
FT TURN 497..499
FT /evidence="ECO:0007829|PDB:1F0L"
FT STRAND 500..507
FT /evidence="ECO:0007829|PDB:1F0L"
FT STRAND 509..512
FT /evidence="ECO:0007829|PDB:1F0L"
FT STRAND 517..525
FT /evidence="ECO:0007829|PDB:1F0L"
FT TURN 533..535
FT /evidence="ECO:0007829|PDB:1F0L"
FT STRAND 540..550
FT /evidence="ECO:0007829|PDB:1F0L"
FT STRAND 553..562
FT /evidence="ECO:0007829|PDB:1F0L"
FT STRAND 564..566
FT /evidence="ECO:0007829|PDB:1F0L"
SQ SEQUENCE 567 AA; 61602 MW; CAF82A75EA693FF8 CRC64;
MLVRGYVVSR KLFASILIGA LLGIGAPPSA HAGADDVVDS SKSFVMENFS SYHGTKPGYV
DSIQKGIQKP KSGTQGNYDD DWKGFYSTDN KYDAAGYSVD NENPLSGKAG GVVKVTYPGL
TKVLALKVDN AETIKKELGL SLTEPLMEQV GTEEFIKRFG DGASRVVLSL PFAEGSSSVE
YINNWEQAKA LSVELEINFE TRGKRGQDAM YEYMAQACAG NRVRRSVGSS LSCINLDWDV
IRDKTKTKIE SLKEHGPIKN KMSESPNKTV SEEKAKQYLE EFHQTALEHP ELSELKTVTG
TNPVFAGANY AAWAVNVAQV IDSETADNLE KTTAALSILP GIGSVMGIAD GAVHHNTEEI
VAQSIALSSL MVAQAIPLVG ELVDIGFAAY NFVESIINLF QVVHNSYNRP AYSPGHKTQP
FLHDGYAVSW NTVEDSIIRT GFQGESGHDI KITAENTPLP IAGVLLPTIP GKLDVNKSKT
HISVNGRKIR MRCRAIDGDV TFCRPKSPVY VGNGVHANLH VAFHRSSSEK IHSNEISSDS
IGVLGYQKTV DHTKVNSKLS LFFEIKS
