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 24-JAN-2024, entry version 137. 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 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}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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:MONOMER-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:0016779; F:nucleotidyltransferase activity; IEA:UniProtKB-KW. DR GO; GO:0008320; F:protein transmembrane transporter activity; TAS:Reactome. DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW. DR Gene3D; 3.90.175.10; Diphtheria Toxin, domain 1; 1. DR Gene3D; 2.60.40.700; Diphtheria toxin, receptor-binding domain; 1. DR Gene3D; 1.10.490.40; Diphtheria toxin, translocation domain; 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 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; SSF56399; ADP-ribosylation; 1. DR SUPFAM; SSF49380; Diphtheria toxin, C-terminal domain; 1. DR SUPFAM; SSF56845; Diphtheria toxin, middle domain; 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 //