BXA1_CLOBH
ID BXA1_CLOBH Reviewed; 1296 AA.
AC P0DPI1; A5HZZ9; A7G1U9; P01561; P10845; P18639;
DT 18-JUL-2018, integrated into UniProtKB/Swiss-Prot.
DT 18-JUL-2018, sequence version 1.
DT 03-AUG-2022, entry version 23.
DE RecName: Full=Botulinum neurotoxin type A;
DE Short=BoNT/A;
DE AltName: Full=Bontoxilysin-A;
DE Short=BOTOX;
DE Contains:
DE RecName: Full=Botulinum neurotoxin A light chain;
DE Short=LC;
DE EC=3.4.24.69 {ECO:0000269|PubMed:8103915};
DE Contains:
DE RecName: Full=Botulinum neurotoxin A heavy chain;
DE Short=HC;
DE Flags: Precursor;
GN Name=botA {ECO:0000303|PubMed:17519437};
GN Synonyms=bna {ECO:0000303|PubMed:2669749};
GN OrderedLocusNames=CBO0806, CLC_0862;
OS Clostridium botulinum (strain Hall / ATCC 3502 / NCTC 13319 / Type A).
OC Bacteria; Firmicutes; Clostridia; Eubacteriales; Clostridiaceae;
OC Clostridium.
OX NCBI_TaxID=441771;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Hall / ATCC 3502 / NCTC 13319 / Type A;
RX PubMed=17519437; DOI=10.1101/gr.6282807;
RA Sebaihia M., Peck M.W., Minton N.P., Thomson N.R., Holden M.T.G.,
RA Mitchell W.J., Carter A.T., Bentley S.D., Mason D.R., Crossman L.,
RA Paul C.J., Ivens A., Wells-Bennik M.H.J., Davis I.J., Cerdeno-Tarraga A.M.,
RA Churcher C., Quail M.A., Chillingworth T., Feltwell T., Fraser A.,
RA Goodhead I., Hance Z., Jagels K., Larke N., Maddison M., Moule S.,
RA Mungall K., Norbertczak H., Rabbinowitsch E., Sanders M., Simmonds M.,
RA White B., Whithead S., Parkhill J.;
RT "Genome sequence of a proteolytic (Group I) Clostridium botulinum strain
RT Hall A and comparative analysis of the clostridial genomes.";
RL Genome Res. 17:1082-1092(2007).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Hall / ATCC 3502 / NCTC 13319 / Type A;
RX PubMed=18060065; DOI=10.1371/journal.pone.0001271;
RA Smith T.J., Hill K.K., Foley B.T., Detter J.C., Munk A.C., Bruce D.C.,
RA Doggett N.A., Smith L.A., Marks J.D., Xie G., Brettin T.S.;
RT "Analysis of the neurotoxin complex genes in Clostridium botulinum A1-A4
RT and B1 strains: BoNT/A3, /Ba4 and /B1 clusters are located within
RT plasmids.";
RL PLoS ONE 2:E1271-E1271(2007).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-35.
RC STRAIN=Hall / Type A;
RX PubMed=2669749; DOI=10.1016/0006-291x(89)90828-0;
RA Betley M.J., Somers E., Dasgupta B.R.;
RT "Characterization of botulinum type A neurotoxin gene: delineation of the
RT N-terminal encoding region.";
RL Biochem. Biophys. Res. Commun. 162:1388-1395(1989).
RN [4]
RP PROTEIN SEQUENCE OF 449-475 AND 873-896.
RC STRAIN=Hall / Type A;
RX PubMed=3178218; DOI=10.1016/0003-9861(88)90244-5;
RA Sathymoorthy V., Dasgupta B.R., Foley J., Niece R.L.;
RT "Botulinum neurotoxin type A: cleavage of the heavy chain into two halves
RT and their partial sequences.";
RL Arch. Biochem. Biophys. 266:142-151(1988).
RN [5]
RP PROTEIN SEQUENCE OF 867-880 AND 1148-1219.
RC STRAIN=Hall / Type A;
RX PubMed=8397793; DOI=10.1007/bf01028197;
RA Gimenez J.A., DasGupta B.R.;
RT "Botulinum type A neurotoxin digested with pepsin yields 132, 97, 72, 45,
RT 42, and 18 kD fragments.";
RL J. Protein Chem. 12:351-363(1993).
RN [6]
RP RELEASED AS DICHAIN.
RC STRAIN=Hall / Type A;
RX PubMed=4030755; DOI=10.1016/s0021-9258(19)85105-0;
RA Sathyamoorthy V., DasGupta B.R.;
RT "Separation, purification, partial characterization and comparison of the
RT heavy and light chains of botulinum neurotoxin types A, B, and E.";
RL J. Biol. Chem. 260:10461-10466(1985).
RN [7]
RP HOST RANGE, AND EPIDEMIOLOGY.
RX PubMed=1431246; DOI=10.1093/infdis/166.6.1281;
RA Woodruff B.A., Griffin P.M., McCroskey L.M., Smart J.F., Wainwright R.B.,
RA Bryant R.G., Hutwagner L.C., Hatheway C.L.;
RT "Clinical and laboratory comparison of botulism from toxin types A, B, and
RT E in the United States, 1975-1988.";
RL J. Infect. Dis. 166:1281-1286(1992).
RN [8]
RP FUNCTION (BOTULINUM NEUROTOXIN TYPE A AND BOTULINUM NEUROTOXIN A LIGHT
RP CHAIN), IDENTIFICATION OF SUBSTRATE, CATALYTIC ACTIVITY, ACTIVITY
RP REGULATION, SUBCELLULAR LOCATION (BOTULINUM NEUROTOXIN A LIGHT CHAIN), AND
RP MUTAGENESIS OF GLU-224.
RC STRAIN=Hall / Type A;
RX PubMed=8103915; DOI=10.1038/365160a0;
RA Blasi J., Chapman E.R., Link E., Binz T., Yamasaki S., De Camilli P.,
RA Suedhof T.C., Niemann H., Jahn R.;
RT "Botulinum neurotoxin A selectively cleaves the synaptic protein SNAP-25.";
RL Nature 365:160-163(1993).
RN [9]
RP IDENTIFICATION OF SUBSTRATE (BOTULINUM NEUROTOXIN TYPE A AND BOTULINUM
RP NEUROTOXIN A LIGHT CHAIN), IDENTIFICATION OF SUBSTRATE, CATALYTIC ACTIVITY,
RP AND SUBCELLULAR LOCATION (BOTULINUM NEUROTOXIN A LIGHT CHAIN).
RC STRAIN=Hall / Type A;
RX PubMed=8294407; DOI=10.1016/s0021-9258(17)42071-0;
RA Binz T., Blasi J., Yamasaki S., Baumeister A., Link E., Suedhof T.C.,
RA Jahn R., Niemann H.;
RT "Proteolysis of SNAP-25 by types E and A botulinal neurotoxins.";
RL J. Biol. Chem. 269:1617-1620(1994).
RN [10]
RP FUNCTION (BOTULINUM NEUROTOXIN A HEAVY CHAIN), AND GANGLIOSIDE-BINDING.
RC STRAIN=Hall / Type A;
RX PubMed=21849494; DOI=10.1074/jbc.m111.272054;
RA Benson M.A., Fu Z., Kim J.J., Baldwin M.R.;
RT "Unique ganglioside recognition strategies for clostridial neurotoxins.";
RL J. Biol. Chem. 286:34015-34022(2011).
RN [11]
RP REVIEW.
RX PubMed=28356439; DOI=10.1124/pr.116.012658;
RA Pirazzini M., Rossetto O., Eleopra R., Montecucco C.;
RT "Botulinum neurotoxins: Biology, pharmacology, and toxicology.";
RL Pharmacol. Rev. 69:200-235(2017).
RN [12] {ECO:0007744|PDB:3BTA}
RP X-RAY CRYSTALLOGRAPHY (3.3 ANGSTROMS) OF 2-1296, COFACTOR, SUBUNIT,
RP SUBCELLULAR LOCATION (BOTULINUM NEUROTOXIN A LIGHT CHAIN AND BOTULINUM
RP NEUROTOXIN A HEAVY CHAIN), DOMAIN, AND DISULFIDE BOND.
RC STRAIN=Hall / Type A;
RX PubMed=9783750; DOI=10.1038/2338;
RA Lacy D.B., Tepp W., Cohen A.C., Dasgupta B.R., Stevens R.C.;
RT "Crystal structure of botulinum neurotoxin type A and implications for
RT toxicity.";
RL Nat. Struct. Biol. 5:898-902(1998).
RN [13] {ECO:0007744|PDB:2NYY, ECO:0007744|PDB:2NZ9}
RP X-RAY CRYSTALLOGRAPHY (2.61 ANGSTROMS) OF 2-1296 IN COMPLEX WITH ZINC AND
RP NEUTRALIZING ANTIBODY FRAGMENTS, COFACTOR, SUBUNIT, DOMAIN, AND DISULFIDE
RP BONDS.
RC STRAIN=Hall / Type A;
RX PubMed=17173035; DOI=10.1038/nbt1269;
RA Garcia-Rodriguez C., Levy R., Arndt J.W., Forsyth C.M., Razai A., Lou J.,
RA Geren I., Stevens R.C., Marks J.D.;
RT "Molecular evolution of antibody cross-reactivity for two subtypes of type
RT A botulinum neurotoxin.";
RL Nat. Biotechnol. 25:107-116(2007).
RN [14] {ECO:0007744|PDB:3FUO}
RP X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF 871-1296, FUNCTION (BOTULINUM
RP NEUROTOXIN TYPE A), FUNCTION (BOTULINUM NEUROTOXIN A HEAVY CHAIN),
RP SUBCELLULAR LOCATION (BOTULINUM NEUROTOXIN A HEAVY CHAIN), AND DOMAIN.
RC STRAIN=Hall / Type A;
RX PubMed=19476346; DOI=10.1021/bi9002138;
RA Fu Z., Chen C., Barbieri J.T., Kim J.J., Baldwin M.R.;
RT "Glycosylated SV2 and gangliosides as dual receptors for botulinum
RT neurotoxin serotype F.";
RL Biochemistry 48:5631-5641(2009).
RN [15] {ECO:0007744|PDB:3QIX, ECO:0007744|PDB:3QIY, ECO:0007744|PDB:3QIZ, ECO:0007744|PDB:3QJ0}
RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 3-424 IN COMPLEX WITH ZINC AND
RP INHIBITORS, COFACTOR, AND ACTIVITY REGULATION.
RC STRAIN=Hall / ATCC 3502 / NCTC 13319 / Type A;
RX PubMed=21434688; DOI=10.1021/bi2001483;
RA Thompson A.A., Jiao G.S., Kim S., Thai A., Cregar-Hernandez L.,
RA Margosiak S.A., Johnson A.T., Han G.W., O'Malley S., Stevens R.C.;
RT "Structural characterization of three novel hydroxamate-based zinc
RT chelating inhibitors of the Clostridium botulinum serotype A neurotoxin
RT light chain metalloprotease reveals a compact binding site resulting from
RT 60/70 loop flexibility.";
RL Biochemistry 50:4019-4028(2011).
CC -!- FUNCTION: [Botulinum neurotoxin type A]: Botulinum toxin causes flaccid
CC paralysis by inhibiting neurotransmitter (acetylcholine) release from
CC the presynaptic membranes of nerve terminals of the eukaryotic host
CC skeletal and autonomic nervous system, with frequent heart or
CC respiratory failure (PubMed:8103915). Precursor of botulinum neurotoxin
CC A which has 2 coreceptors; complex polysialylated gangliosides found on
CC neural tissue and specific membrane-anchored proteins of synaptic
CC vesicles (By similarity). Receptor proteins are exposed on host
CC presynaptic cell membrane during neurotransmitter release, when the
CC toxin heavy chain (HC) binds to them (PubMed:19476346). Upon synaptic
CC vesicle recycling the toxin is taken up via the endocytic pathway (By
CC similarity). When the pH of the toxin-containing endosome drops a
CC structural rearrangement occurs so that the N-terminus of the HC forms
CC pores that allows the light chain (LC) to translocate into the cytosol
CC (By similarity). Once in the cytosol the disulfide bond linking the 2
CC subunits is reduced and LC cleaves its target protein on synaptic
CC vesicles, preventing their fusion with the cytoplasmic membrane and
CC thus neurotransmitter release (By similarity).
CC {ECO:0000250|UniProtKB:P0DPI0, ECO:0000269|PubMed:19476346,
CC ECO:0000269|PubMed:8103915}.
CC -!- FUNCTION: [Botulinum neurotoxin A light chain]: Has proteolytic
CC activity (PubMed:8103915, PubMed:8294407). In vitro the whole toxin is
CC reduced to release LC (PubMed:8103915, PubMed:8294407). After
CC translocation into the eukaryotic host cytosol, LC hydrolyzes the 197-
CC Gln-|-Arg-198 bond in SNAP25, blocking neurotransmitter release
CC (PubMed:8103915, PubMed:8294407). {ECO:0000269|PubMed:8103915,
CC ECO:0000269|PubMed:8294407, ECO:0000305|PubMed:19476346}.
CC -!- FUNCTION: [Botulinum neurotoxin A heavy chain]: Responsible for host
CC epithelial cell transcytosis, host nerve cell targeting and
CC translocation of light chain (LC) into host cytosol. Composed of 3
CC subdomains; the translocation domain (TD), and N-terminus and C-
CC terminus of the receptor-binding domain (RBD) (PubMed:9783750,
CC PubMed:17173035). The RBD is responsible for the adherence of the toxin
CC to the cell surface. It simultaneously recognizes 2 coreceptors;
CC polysialated gangliosides and synaptic vesicle glycoproteins SV2A, SV2B
CC and SV2C in close proximity on host synaptic vesicles (By similarity).
CC The RBD specifically recognizes the N-linked glycan on 'Asn-559' of
CC SV2A, SV2B and SV2C (By similarity). Isolated HC binds to host
CC synaptosomes, significantly decreases uptake and toxicity of whole
CC BoNT/A (PubMed:19476346). Binds ganglioside GD1a in vitro
CC (PubMed:21849494). The N-terminus of the TD wraps an extended belt
CC around the perimeter of the LC, protecting Zn(2+) in the active site;
CC it may also prevent premature LC dissociation from the translocation
CC channel and to protect toxin prior to translocation (PubMed:9783750).
CC The TD inserts into synaptic vesicle membrane to allow translocation
CC into the host cytosol (By similarity). {ECO:0000250|UniProtKB:P0DPI0,
CC ECO:0000269|PubMed:17173035, ECO:0000269|PubMed:19476346,
CC ECO:0000269|PubMed:21849494, ECO:0000269|PubMed:9783750}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Limited hydrolysis of proteins of the neuroexocytosis
CC apparatus, synaptobrevins, SNAP25 or syntaxin. No detected action on
CC small molecule substrates.; EC=3.4.24.69;
CC Evidence={ECO:0000269|PubMed:8103915, ECO:0000269|PubMed:8294407};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000269|PubMed:17173035, ECO:0000269|PubMed:21434688,
CC ECO:0000269|PubMed:9783750};
CC Note=Binds 1 zinc ion per subunit (PubMed:9783750, PubMed:17173035,
CC PubMed:21434688). {ECO:0000269|PubMed:17173035,
CC ECO:0000269|PubMed:21434688, ECO:0000269|PubMed:9783750};
CC -!- ACTIVITY REGULATION: SNAP25 proteolysis is inhibited by 1,10-
CC phenanthroline and 2,2'-dipyridyl but not EDTA (PubMed:8103915).
CC Inhibited by hydroxamate compounds with halogenated benzene-containing
CC arms which directly bind the zinc ion (PubMed:21434688).
CC {ECO:0000269|PubMed:21434688, ECO:0000269|PubMed:8103915}.
CC -!- SUBUNIT: Heterodimer; disulfide-linked heterodimer of a light chain
CC (LC) and a heavy chain (HC) (PubMed:9783750, PubMed:17173035).
CC Interacts with host synaptic vesicle glycoproteins SV2A, SV2B and SV2C
CC which serve as coreceptors (By similarity). Glycosylation of 'Asn-559'
CC in SV2C probably contributes a 12-fold increase in affinity to this
CC interaction (By similarity). Depolarization of target tissue with high
CC levels of K(+) leads to greater levels of receptor exposure
CC (PubMed:19476346). {ECO:0000250|UniProtKB:P0DPI0,
CC ECO:0000269|PubMed:17173035, ECO:0000269|PubMed:19476346,
CC ECO:0000269|PubMed:9783750}.
CC -!- SUBCELLULAR LOCATION: [Botulinum neurotoxin A light chain]: Secreted
CC {ECO:0000305|PubMed:9783750}. Host cytoplasm, host cytosol
CC {ECO:0000305|PubMed:8103915, ECO:0000305|PubMed:8294407}.
CC -!- SUBCELLULAR LOCATION: [Botulinum neurotoxin A heavy chain]: Secreted
CC {ECO:0000305|PubMed:9783750}. Host synapse, host presynaptic cell
CC membrane {ECO:0000269|PubMed:19476346}. Host cytoplasmic vesicle, host
CC secretory vesicle, host synaptic vesicle membrane
CC {ECO:0000305|PubMed:19476346}; Multi-pass membrane protein
CC {ECO:0000305}.
CC -!- DOMAIN: [Botulinum neurotoxin A light chain]: Has protease activity
CC (PubMed:8103915, PubMed:8294407). {ECO:0000269|PubMed:8103915,
CC ECO:0000269|PubMed:8294407}.
CC -!- DOMAIN: [Botulinum neurotoxin A heavy chain]: Has 3 functional domains;
CC the translocation domain (TD) and the receptor-binding domain (RBD)
CC which is further subdivided into N- and C-terminal domains (N-RBD and
CC C-RBD) (PubMed:17173035, PubMed:19476346). The N-terminus of the TD
CC wraps an extended belt around the perimeter of the LC, protecting
CC Zn(2+) in the active site and may be a pseudosubstrate inhibitor which
CC serves as an intramolecular chaperone for the LC prior to its
CC translocation into the host cytosol (PubMed:9783750). The RBD binds
CC transiently exposed coreceptors on the host presynaptic cell membrane
CC (PubMed:19476346). {ECO:0000269|PubMed:17173035,
CC ECO:0000269|PubMed:19476346, ECO:0000269|PubMed:9783750}.
CC -!- PTM: In a bacterial culture the precursor chain is initally cleaved on
CC the amino side of Gly-445 and is processed more slowly between Lys-448
CC and Ala-449 to give the final mature heavy chain sequence.
CC {ECO:0000250|UniProtKB:P0DPI0}.
CC -!- PHARMACEUTICAL: Available under the name Botox (onabotulinumtoxinA,
CC Allergan), Dysport (abobotulinumtoxinA, Ipsen Biopharmaceuticals) and
CC Xeomin (incobotulinumtoxinA, Merz Pharmaceuticals) for the treatment of
CC strabismus and blepharospasm associated with dystonia and cervical
CC dystonia. Used for the treatment of hemifacial spasm and a number of
CC other neurological disorders characterized by abnormal muscle
CC contraction. It is also used cosmetically to smooth facial wrinkles.
CC {ECO:0000305|PubMed:28356439}.
CC -!- MISCELLANEOUS: There are seven antigenically distinct forms of
CC botulinum neurotoxin: Types A, B, C, D, E, F, and G; new subtypes are
CC quite frequent.
CC -!- MISCELLANEOUS: Botulism poisoning is usually food-borne, either by
CC ingesting toxin or bacterial-contaminated food, or less frequently by
CC inhalation poisoning. In both cases the neurotoxin binds to the apical
CC surface of epithelial cells in the gut or airway. Toxin undergoes
CC receptor-mediated endocytosis (using a different receptor than on
CC target nerve cells), transcytosis across the epithelial cells and
CC release into the general circulation. Once in the general circulation
CC it binds to its target cells. {ECO:0000250|UniProtKB:P0DPI0}.
CC -!- MISCELLANEOUS: Types A, B and E are the most frequent cause of adult
CC human foodborne botulism; type A is the most severe, while type E has
CC the shortest incubation period (PubMed:1431246).
CC {ECO:0000269|PubMed:1431246}.
CC -!- MISCELLANEOUS: Neurotoxin type A is released from bacteria in the two-
CC chain form (PubMed:4030755). {ECO:0000269|PubMed:4030755}.
CC -!- MISCELLANEOUS: Neutralizing antibodies are used to treat botulism; in
CC at least 2 cases they bind to HC. {ECO:0000269|PubMed:17173035}.
CC -!- SIMILARITY: Belongs to the peptidase M27 family. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=BOTOX product information Web site;
CC URL="https://www.botox.com/";
CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=From sausages to wrinkles
CC - Issue 19 of February 2002;
CC URL="https://web.expasy.org/spotlight/back_issues/019";
CC -!- WEB RESOURCE: Name=BotDB - A Database Resource for Clostridial
CC Neurotoxins;
CC URL="https://botdb.abcc.ncifcrf.gov/";
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DR EMBL; AM412317; CAL82360.1; -; Genomic_DNA.
DR EMBL; CP000727; ABS38337.1; -; Genomic_DNA.
DR EMBL; M27892; AAA23269.1; -; Genomic_DNA.
DR PIR; A35294; BTCLAB.
DR RefSeq; WP_011948511.1; NC_009698.1.
DR RefSeq; YP_001253342.1; NC_009495.1.
DR RefSeq; YP_001386738.1; NC_009698.1.
DR PDB; 2NYY; X-ray; 2.61 A; A=2-1296.
DR PDB; 2NZ9; X-ray; 3.79 A; A/B=2-1296.
DR PDB; 3BTA; X-ray; 3.20 A; A=2-1296.
DR PDB; 3BWI; X-ray; 1.70 A; A=1-424.
DR PDB; 3C88; X-ray; 1.60 A; A=1-424.
DR PDB; 3C89; X-ray; 1.58 A; A=1-424.
DR PDB; 3C8A; X-ray; 1.52 A; A=1-424.
DR PDB; 3C8B; X-ray; 1.47 A; A=1-424.
DR PDB; 3DDA; X-ray; 1.50 A; A=1-424.
DR PDB; 3DDB; X-ray; 1.60 A; A=1-424.
DR PDB; 3DS9; X-ray; 1.76 A; A=1-417.
DR PDB; 3DSE; X-ray; 1.90 A; A=1-417.
DR PDB; 3FUO; X-ray; 1.80 A; A=871-1296.
DR PDB; 3K3Q; X-ray; 2.60 A; B=3-250, C=251-425.
DR PDB; 3QIX; X-ray; 2.41 A; A/B=3-424.
DR PDB; 3QIY; X-ray; 2.30 A; A=3-424.
DR PDB; 3QIZ; X-ray; 2.00 A; A=3-424.
DR PDB; 3QJ0; X-ray; 2.30 A; A=3-424.
DR PDB; 3QW5; X-ray; 1.60 A; A=1-424.
DR PDB; 3QW6; X-ray; 1.60 A; A=1-424.
DR PDB; 3QW7; X-ray; 1.50 A; A=1-424.
DR PDB; 3QW8; X-ray; 1.60 A; A=1-424.
DR PDB; 4EJ5; X-ray; 1.87 A; A=1-425.
DR PDB; 4EL4; X-ray; 1.20 A; A=1-425.
DR PDB; 4ELC; X-ray; 1.80 A; A=1-425.
DR PDB; 4KS6; X-ray; 1.93 A; A=1-425.
DR PDB; 4KTX; X-ray; 2.59 A; A=1-425.
DR PDB; 4KUF; X-ray; 1.70 A; A=1-425.
DR PDB; 4ZJX; X-ray; 1.94 A; A=1-424.
DR PDB; 5L21; X-ray; 1.68 A; A=872-1296.
DR PDB; 6UI1; X-ray; 2.20 A; A=1-871.
DR PDB; 6UL6; X-ray; 2.02 A; A=1-871.
DR PDB; 7KY2; X-ray; 2.78 A; A/B=3-420.
DR PDBsum; 2NYY; -.
DR PDBsum; 2NZ9; -.
DR PDBsum; 3BTA; -.
DR PDBsum; 3BWI; -.
DR PDBsum; 3C88; -.
DR PDBsum; 3C89; -.
DR PDBsum; 3C8A; -.
DR PDBsum; 3C8B; -.
DR PDBsum; 3DDA; -.
DR PDBsum; 3DDB; -.
DR PDBsum; 3DS9; -.
DR PDBsum; 3DSE; -.
DR PDBsum; 3FUO; -.
DR PDBsum; 3K3Q; -.
DR PDBsum; 3QIX; -.
DR PDBsum; 3QIY; -.
DR PDBsum; 3QIZ; -.
DR PDBsum; 3QJ0; -.
DR PDBsum; 3QW5; -.
DR PDBsum; 3QW6; -.
DR PDBsum; 3QW7; -.
DR PDBsum; 3QW8; -.
DR PDBsum; 4EJ5; -.
DR PDBsum; 4EL4; -.
DR PDBsum; 4ELC; -.
DR PDBsum; 4KS6; -.
DR PDBsum; 4KTX; -.
DR PDBsum; 4KUF; -.
DR PDBsum; 4ZJX; -.
DR PDBsum; 5L21; -.
DR PDBsum; 6UI1; -.
DR PDBsum; 6UL6; -.
DR PDBsum; 7KY2; -.
DR AlphaFoldDB; P0DPI1; -.
DR SMR; P0DPI1; -.
DR BindingDB; P0DPI1; -.
DR ChEMBL; CHEMBL5344; -.
DR UniLectin; P0DPI1; -.
DR ABCD; P0DPI1; 24 sequenced antibodies.
DR GeneID; 5185061; -.
DR KEGG; cbh:CLC_0862; -.
DR KEGG; cbo:CBO0806; -.
DR OMA; DEGYNKA; -.
DR BRENDA; 3.4.24.69; 1462.
DR PRO; PR:P0DPI1; -.
DR Proteomes; UP000001986; Chromosome.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0044161; C:host cell cytoplasmic vesicle; IEA:UniProtKB-SubCell.
DR GO; GO:0044164; C:host cell cytosol; IEA:UniProtKB-SubCell.
DR GO; GO:0044156; C:host cell junction; IEA:UniProtKB-KW.
DR GO; GO:0044231; C:host cell presynaptic membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0004222; F:metalloendopeptidase activity; IEA:UniProtKB-EC.
DR GO; GO:0008320; F:protein transmembrane transporter activity; IEA:InterPro.
DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0046929; P:negative regulation of neurotransmitter secretion; IEA:InterPro.
DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR Gene3D; 1.20.1120.10; -; 1.
DR InterPro; IPR000395; Bot/tetX_LC.
DR InterPro; IPR036248; Clostridium_toxin_transloc.
DR InterPro; IPR013320; ConA-like_dom_sf.
DR InterPro; IPR011065; Kunitz_inhibitor_STI-like_sf.
DR InterPro; IPR013104; Toxin_rcpt-bd_C.
DR InterPro; IPR012928; Toxin_rcpt-bd_N.
DR InterPro; IPR012500; Toxin_trans.
DR Pfam; PF01742; Peptidase_M27; 1.
DR Pfam; PF07951; Toxin_R_bind_C; 1.
DR Pfam; PF07953; Toxin_R_bind_N; 1.
DR Pfam; PF07952; Toxin_trans; 1.
DR PRINTS; PR00760; BONTOXILYSIN.
DR SUPFAM; SSF49899; SSF49899; 1.
DR SUPFAM; SSF50386; SSF50386; 1.
DR SUPFAM; SSF58091; SSF58091; 1.
DR PROSITE; PS00142; ZINC_PROTEASE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Direct protein sequencing; Disulfide bond;
KW Host cell membrane; Host cytoplasm; Host cytoplasmic vesicle;
KW Host membrane; Host synapse; Hydrolase; Membrane; Metal-binding;
KW Metalloprotease; Neurotoxin; Pharmaceutical; Protease; Reference proteome;
KW Secreted; Toxin; Transmembrane; Transmembrane helix; Virulence; Zinc.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:P0DPI0"
FT CHAIN 2..1296
FT /note="Botulinum neurotoxin type A"
FT /id="PRO_0000444903"
FT CHAIN 2..448
FT /note="Botulinum neurotoxin A light chain"
FT /id="PRO_0000308906"
FT CHAIN 449..1296
FT /note="Botulinum neurotoxin A heavy chain"
FT /id="PRO_0000308907"
FT TRANSMEM 627..647
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 656..676
FT /note="Helical"
FT /evidence="ECO:0000255"
FT REGION 449..872
FT /note="Translocation domain (TD)"
FT /evidence="ECO:0000305|PubMed:17173035,
FT ECO:0000305|PubMed:9783750"
FT REGION 492..545
FT /note="Belt"
FT /evidence="ECO:0000250|UniProtKB:P0DPI0"
FT REGION 873..1092
FT /note="N-terminus of receptor binding domain (N-RBD)"
FT /evidence="ECO:0000305|PubMed:17173035,
FT ECO:0000305|PubMed:9783750"
FT REGION 1093..1296
FT /note="C-terminus of receptor binding domain (C-RBD)"
FT /evidence="ECO:0000305|PubMed:17173035,
FT ECO:0000305|PubMed:9783750"
FT MOTIF 1264..1267
FT /note="Host ganglioside-binding motif"
FT /evidence="ECO:0000250|UniProtKB:P0DPI0"
FT ACT_SITE 224
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10095"
FT BINDING 223
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10095,
FT ECO:0000269|PubMed:17173035, ECO:0000305|PubMed:9783750,
FT ECO:0007744|PDB:2NYY, ECO:0007744|PDB:2NZ9,
FT ECO:0007744|PDB:3BTA, ECO:0007744|PDB:3QIX,
FT ECO:0007744|PDB:3QIY, ECO:0007744|PDB:3QIZ,
FT ECO:0007744|PDB:3QJ0"
FT BINDING 227
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10095,
FT ECO:0000269|PubMed:17173035, ECO:0000305|PubMed:9783750,
FT ECO:0007744|PDB:2NYY, ECO:0007744|PDB:2NZ9,
FT ECO:0007744|PDB:3BTA, ECO:0007744|PDB:3QIX,
FT ECO:0007744|PDB:3QIY, ECO:0007744|PDB:3QIZ,
FT ECO:0007744|PDB:3QJ0"
FT BINDING 262
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10095,
FT ECO:0000269|PubMed:17173035, ECO:0007744|PDB:2NYY,
FT ECO:0007744|PDB:2NZ9, ECO:0007744|PDB:3BTA,
FT ECO:0007744|PDB:3QIX, ECO:0007744|PDB:3QIY,
FT ECO:0007744|PDB:3QIZ, ECO:0007744|PDB:3QJ0"
FT DISULFID 430..454
FT /note="Interchain (between light and heavy chains)"
FT /evidence="ECO:0000269|PubMed:17173035,
FT ECO:0000269|PubMed:9783750, ECO:0007744|PDB:2NYY,
FT ECO:0007744|PDB:2NZ9, ECO:0007744|PDB:3BTA"
FT DISULFID 1235..1280
FT /evidence="ECO:0000269|PubMed:17173035,
FT ECO:0000269|PubMed:9783750, ECO:0007744|PDB:2NZ9,
FT ECO:0007744|PDB:3BTA"
FT MUTAGEN 224
FT /note="E->K,Q: Light chain no longer cleaves SNAP25."
FT /evidence="ECO:0000269|PubMed:8103915"
FT CONFLICT 876
FT /note="T -> L (in Ref. 4; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 892
FT /note="S -> K (in Ref. 4; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 1218
FT /note="S -> Y (in Ref. 5; AA sequence)"
FT /evidence="ECO:0000305"
FT STRAND 3..6
FT /evidence="ECO:0007829|PDB:3C8B"
FT STRAND 16..23
FT /evidence="ECO:0007829|PDB:4EL4"
FT STRAND 26..28
FT /evidence="ECO:0007829|PDB:3DDA"
FT STRAND 33..39
FT /evidence="ECO:0007829|PDB:4EL4"
FT STRAND 42..48
FT /evidence="ECO:0007829|PDB:4EL4"
FT STRAND 51..53
FT /evidence="ECO:0007829|PDB:3C88"
FT HELIX 54..56
FT /evidence="ECO:0007829|PDB:3C8B"
FT TURN 64..66
FT /evidence="ECO:0007829|PDB:3C8B"
FT TURN 68..70
FT /evidence="ECO:0007829|PDB:3DS9"
FT TURN 75..78
FT /evidence="ECO:0007829|PDB:4EL4"
FT HELIX 81..99
FT /evidence="ECO:0007829|PDB:4EL4"
FT HELIX 102..113
FT /evidence="ECO:0007829|PDB:4EL4"
FT STRAND 126..128
FT /evidence="ECO:0007829|PDB:4EL4"
FT HELIX 131..133
FT /evidence="ECO:0007829|PDB:4EL4"
FT STRAND 134..138
FT /evidence="ECO:0007829|PDB:4EL4"
FT TURN 140..142
FT /evidence="ECO:0007829|PDB:7KY2"
FT STRAND 144..148
FT /evidence="ECO:0007829|PDB:4EL4"
FT STRAND 150..155
FT /evidence="ECO:0007829|PDB:4EL4"
FT STRAND 164..166
FT /evidence="ECO:0007829|PDB:4EL4"
FT TURN 170..172
FT /evidence="ECO:0007829|PDB:4ELC"
FT TURN 175..177
FT /evidence="ECO:0007829|PDB:4EL4"
FT STRAND 184..187
FT /evidence="ECO:0007829|PDB:4EL4"
FT STRAND 190..196
FT /evidence="ECO:0007829|PDB:4EL4"
FT HELIX 200..203
FT /evidence="ECO:0007829|PDB:4EL4"
FT STRAND 211..214
FT /evidence="ECO:0007829|PDB:3DSE"
FT HELIX 217..232
FT /evidence="ECO:0007829|PDB:4EL4"
FT STRAND 242..244
FT /evidence="ECO:0007829|PDB:4EL4"
FT HELIX 249..253
FT /evidence="ECO:0007829|PDB:4EL4"
FT STRAND 257..259
FT /evidence="ECO:0007829|PDB:4EL4"
FT HELIX 260..266
FT /evidence="ECO:0007829|PDB:4EL4"
FT HELIX 268..273
FT /evidence="ECO:0007829|PDB:4EL4"
FT HELIX 276..299
FT /evidence="ECO:0007829|PDB:4EL4"
FT STRAND 305..308
FT /evidence="ECO:0007829|PDB:4EL4"
FT HELIX 310..321
FT /evidence="ECO:0007829|PDB:4EL4"
FT STRAND 327..329
FT /evidence="ECO:0007829|PDB:3QW5"
FT HELIX 335..346
FT /evidence="ECO:0007829|PDB:4EL4"
FT HELIX 351..358
FT /evidence="ECO:0007829|PDB:4EL4"
FT STRAND 366..368
FT /evidence="ECO:0007829|PDB:4EL4"
FT STRAND 372..375
FT /evidence="ECO:0007829|PDB:4EL4"
FT TURN 381..383
FT /evidence="ECO:0007829|PDB:4EL4"
FT TURN 386..388
FT /evidence="ECO:0007829|PDB:4EL4"
FT STRAND 393..395
FT /evidence="ECO:0007829|PDB:3K3Q"
FT STRAND 398..401
FT /evidence="ECO:0007829|PDB:2NYY"
FT HELIX 402..404
FT /evidence="ECO:0007829|PDB:4EL4"
FT TURN 406..409
FT /evidence="ECO:0007829|PDB:4EL4"
FT HELIX 410..412
FT /evidence="ECO:0007829|PDB:4EL4"
FT STRAND 414..418
FT /evidence="ECO:0007829|PDB:4EL4"
FT TURN 420..422
FT /evidence="ECO:0007829|PDB:3QW8"
FT STRAND 425..431
FT /evidence="ECO:0007829|PDB:6UL6"
FT HELIX 433..436
FT /evidence="ECO:0007829|PDB:6UL6"
FT STRAND 453..458
FT /evidence="ECO:0007829|PDB:6UL6"
FT HELIX 459..461
FT /evidence="ECO:0007829|PDB:6UL6"
FT HELIX 468..470
FT /evidence="ECO:0007829|PDB:6UL6"
FT STRAND 479..481
FT /evidence="ECO:0007829|PDB:6UL6"
FT HELIX 496..505
FT /evidence="ECO:0007829|PDB:6UL6"
FT STRAND 542..547
FT /evidence="ECO:0007829|PDB:6UL6"
FT HELIX 550..555
FT /evidence="ECO:0007829|PDB:6UL6"
FT STRAND 563..565
FT /evidence="ECO:0007829|PDB:2NYY"
FT STRAND 567..570
FT /evidence="ECO:0007829|PDB:6UL6"
FT HELIX 572..577
FT /evidence="ECO:0007829|PDB:6UL6"
FT STRAND 581..583
FT /evidence="ECO:0007829|PDB:6UL6"
FT HELIX 588..595
FT /evidence="ECO:0007829|PDB:6UL6"
FT HELIX 600..602
FT /evidence="ECO:0007829|PDB:6UL6"
FT HELIX 603..619
FT /evidence="ECO:0007829|PDB:6UL6"
FT STRAND 625..627
FT /evidence="ECO:0007829|PDB:6UL6"
FT STRAND 630..633
FT /evidence="ECO:0007829|PDB:6UI1"
FT HELIX 637..641
FT /evidence="ECO:0007829|PDB:6UL6"
FT HELIX 643..645
FT /evidence="ECO:0007829|PDB:6UL6"
FT HELIX 649..659
FT /evidence="ECO:0007829|PDB:6UL6"
FT HELIX 660..664
FT /evidence="ECO:0007829|PDB:6UL6"
FT STRAND 679..681
FT /evidence="ECO:0007829|PDB:6UL6"
FT HELIX 688..720
FT /evidence="ECO:0007829|PDB:6UL6"
FT HELIX 722..751
FT /evidence="ECO:0007829|PDB:6UL6"
FT HELIX 756..762
FT /evidence="ECO:0007829|PDB:6UL6"
FT HELIX 766..799
FT /evidence="ECO:0007829|PDB:6UL6"
FT HELIX 801..825
FT /evidence="ECO:0007829|PDB:6UL6"
FT TURN 826..832
FT /evidence="ECO:0007829|PDB:6UL6"
FT HELIX 834..844
FT /evidence="ECO:0007829|PDB:6UL6"
FT HELIX 853..855
FT /evidence="ECO:0007829|PDB:6UL6"
FT HELIX 860..863
FT /evidence="ECO:0007829|PDB:6UL6"
FT HELIX 872..875
FT /evidence="ECO:0007829|PDB:5L21"
FT STRAND 878..884
FT /evidence="ECO:0007829|PDB:5L21"
FT STRAND 887..890
FT /evidence="ECO:0007829|PDB:5L21"
FT STRAND 897..900
FT /evidence="ECO:0007829|PDB:5L21"
FT STRAND 904..906
FT /evidence="ECO:0007829|PDB:2NYY"
FT STRAND 908..910
FT /evidence="ECO:0007829|PDB:3BTA"
FT STRAND 914..919
FT /evidence="ECO:0007829|PDB:5L21"
FT STRAND 924..927
FT /evidence="ECO:0007829|PDB:5L21"
FT HELIX 930..932
FT /evidence="ECO:0007829|PDB:5L21"
FT STRAND 935..938
FT /evidence="ECO:0007829|PDB:5L21"
FT STRAND 941..948
FT /evidence="ECO:0007829|PDB:5L21"
FT HELIX 955..957
FT /evidence="ECO:0007829|PDB:5L21"
FT STRAND 962..969
FT /evidence="ECO:0007829|PDB:5L21"
FT STRAND 972..979
FT /evidence="ECO:0007829|PDB:5L21"
FT STRAND 982..988
FT /evidence="ECO:0007829|PDB:5L21"
FT STRAND 990..992
FT /evidence="ECO:0007829|PDB:2NYY"
FT STRAND 994..1000
FT /evidence="ECO:0007829|PDB:5L21"
FT STRAND 1003..1007
FT /evidence="ECO:0007829|PDB:5L21"
FT STRAND 1015..1021
FT /evidence="ECO:0007829|PDB:5L21"
FT STRAND 1025..1031
FT /evidence="ECO:0007829|PDB:5L21"
FT STRAND 1034..1040
FT /evidence="ECO:0007829|PDB:5L21"
FT STRAND 1051..1059
FT /evidence="ECO:0007829|PDB:5L21"
FT STRAND 1066..1077
FT /evidence="ECO:0007829|PDB:5L21"
FT HELIX 1081..1091
FT /evidence="ECO:0007829|PDB:5L21"
FT STRAND 1102..1104
FT /evidence="ECO:0007829|PDB:5L21"
FT STRAND 1106..1108
FT /evidence="ECO:0007829|PDB:2NYY"
FT STRAND 1110..1118
FT /evidence="ECO:0007829|PDB:5L21"
FT STRAND 1122..1129
FT /evidence="ECO:0007829|PDB:5L21"
FT STRAND 1134..1138
FT /evidence="ECO:0007829|PDB:5L21"
FT STRAND 1142..1145
FT /evidence="ECO:0007829|PDB:5L21"
FT TURN 1146..1148
FT /evidence="ECO:0007829|PDB:5L21"
FT STRAND 1149..1152
FT /evidence="ECO:0007829|PDB:5L21"
FT STRAND 1160..1164
FT /evidence="ECO:0007829|PDB:5L21"
FT STRAND 1179..1186
FT /evidence="ECO:0007829|PDB:5L21"
FT STRAND 1189..1195
FT /evidence="ECO:0007829|PDB:5L21"
FT STRAND 1202..1205
FT /evidence="ECO:0007829|PDB:5L21"
FT STRAND 1207..1209
FT /evidence="ECO:0007829|PDB:5L21"
FT HELIX 1211..1213
FT /evidence="ECO:0007829|PDB:5L21"
FT STRAND 1220..1223
FT /evidence="ECO:0007829|PDB:5L21"
FT STRAND 1225..1227
FT /evidence="ECO:0007829|PDB:2NYY"
FT TURN 1228..1230
FT /evidence="ECO:0007829|PDB:2NYY"
FT STRAND 1237..1240
FT /evidence="ECO:0007829|PDB:5L21"
FT STRAND 1246..1255
FT /evidence="ECO:0007829|PDB:5L21"
FT STRAND 1258..1264
FT /evidence="ECO:0007829|PDB:5L21"
FT HELIX 1266..1273
FT /evidence="ECO:0007829|PDB:5L21"
FT STRAND 1281..1285
FT /evidence="ECO:0007829|PDB:5L21"
FT TURN 1289..1291
FT /evidence="ECO:0007829|PDB:3FUO"
SQ SEQUENCE 1296 AA; 149426 MW; DEA8CF2754AE43E6 CRC64;
MPFVNKQFNY KDPVNGVDIA YIKIPNAGQM QPVKAFKIHN KIWVIPERDT FTNPEEGDLN
PPPEAKQVPV SYYDSTYLST DNEKDNYLKG VTKLFERIYS TDLGRMLLTS IVRGIPFWGG
STIDTELKVI DTNCINVIQP DGSYRSEELN LVIIGPSADI IQFECKSFGH EVLNLTRNGY
GSTQYIRFSP DFTFGFEESL EVDTNPLLGA GKFATDPAVT LAHELIHAGH RLYGIAINPN
RVFKVNTNAY YEMSGLEVSF EELRTFGGHD AKFIDSLQEN EFRLYYYNKF KDIASTLNKA
KSIVGTTASL QYMKNVFKEK YLLSEDTSGK FSVDKLKFDK LYKMLTEIYT EDNFVKFFKV
LNRKTYLNFD KAVFKINIVP KVNYTIYDGF NLRNTNLAAN FNGQNTEINN MNFTKLKNFT
GLFEFYKLLC VRGIITSKTK SLDKGYNKAL NDLCIKVNNW DLFFSPSEDN FTNDLNKGEE
ITSDTNIEAA EENISLDLIQ QYYLTFNFDN EPENISIENL SSDIIGQLEL MPNIERFPNG
KKYELDKYTM FHYLRAQEFE HGKSRIALTN SVNEALLNPS RVYTFFSSDY VKKVNKATEA
AMFLGWVEQL VYDFTDETSE VSTTDKIADI TIIIPYIGPA LNIGNMLYKD DFVGALIFSG
AVILLEFIPE IAIPVLGTFA LVSYIANKVL TVQTIDNALS KRNEKWDEVY KYIVTNWLAK
VNTQIDLIRK KMKEALENQA EATKAIINYQ YNQYTEEEKN NINFNIDDLS SKLNESINKA
MININKFLNQ CSVSYLMNSM IPYGVKRLED FDASLKDALL KYIYDNRGTL IGQVDRLKDK
VNNTLSTDIP FQLSKYVDNQ RLLSTFTEYI KNIINTSILN LRYESNHLID LSRYASKINI
GSKVNFDPID KNQIQLFNLE SSKIEVILKN AIVYNSMYEN FSTSFWIRIP KYFNSISLNN
EYTIINCMEN NSGWKVSLNY GEIIWTLQDT QEIKQRVVFK YSQMINISDY INRWIFVTIT
NNRLNNSKIY INGRLIDQKP ISNLGNIHAS NNIMFKLDGC RDTHRYIWIK YFNLFDKELN
EKEIKDLYDN QSNSGILKDF WGDYLQYDKP YYMLNLYDPN KYVDVNNVGI RGYMYLKGPR
GSVMTTNIYL NSSLYRGTKF IIKKYASGNK DNIVRNNDRV YINVVVKNKE YRLATNASQA
GVEKILSALE IPDVGNLSQV VVMKSKNDQG ITNKCKMNLQ DNNGNDIGFI GFHQFNNIAK
LVASNWYNRQ IERSSRTLGC SWEFIPVDDG WGERPL
