CTXL_LEIQU
ID CTXL_LEIQU Reviewed; 36 AA.
AC P45639;
DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1995, sequence version 1.
DT 25-MAY-2022, entry version 95.
DE RecName: Full=Chlorotoxin {ECO:0000303|PubMed:12454020, ECO:0000303|PubMed:8383429};
DE Short=CTX;
DE Short=ClTx {ECO:0000303|PubMed:12454020};
DE AltName: INN=Tozuleristide;
OS Leiurus quinquestriatus quinquestriatus (Egyptian scorpion) (Deathstalker
OS scorpion).
OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Chelicerata; Arachnida;
OC Scorpiones; Buthida; Buthoidea; Buthidae; Leiurus.
OX NCBI_TaxID=6885;
RN [1]
RP PROTEIN SEQUENCE, FUNCTION, AND SUBCELLULAR LOCATION.
RC TISSUE=Venom;
RX PubMed=8383429; DOI=10.1152/ajpcell.1993.264.2.c361;
RA Debin J.A., Maggio J.E., Strichartz G.R.;
RT "Purification and characterization of chlorotoxin, a chloride channel
RT ligand from the venom of the scorpion.";
RL Am. J. Physiol. 264:C361-C369(1993).
RN [2]
RP FUNCTION AS MMP-2 BINDING TOXIN.
RX PubMed=12454020; DOI=10.1074/jbc.m205662200;
RA Deshane J., Garner C.C., Sontheimer H.;
RT "Chlorotoxin inhibits glioma cell invasion via matrix metalloproteinase-
RT 2.";
RL J. Biol. Chem. 278:4135-4144(2003).
RN [3]
RP PROBABLE FUNCTION AS CLC3 INHIBITOR, AND REVIEW.
RX PubMed=16520829; DOI=10.1017/s17440925x06000044;
RA McFerrin M.B., Sontheimer H.;
RT "A role for ion channels in glioma cell invasion.";
RL Neuron Glia Biol. 2:39-49(2006).
RN [4]
RP MISCELLANEOUS.
RX PubMed=16877732; DOI=10.1200/jco.2005.05.4569;
RA Mamelak A.N., Rosenfeld S., Bucholz R., Raubitschek A., Nabors L.B.,
RA Fiveash J.B., Shen S., Khazaeli M.B., Colcher D., Liu A., Osman M.,
RA Guthrie B., Schade-Bijur S., Hablitz D.M., Alvarez V.L., Gonda M.A.;
RT "Phase I single-dose study of intracavitary-administered iodine-131-TM-601
RT in adults with recurrent high-grade glioma.";
RL J. Clin. Oncol. 24:3644-3650(2006).
RN [5]
RP BIOTECHNOLOGY.
RX PubMed=17638899; DOI=10.1158/0008-5472.can-06-3948;
RA Veiseh M., Gabikian P., Bahrami S.B., Veiseh O., Zhang M., Hackman R.C.,
RA Ravanpay A.C., Stroud M.R., Kusuma Y., Hansen S.J., Kwok D., Munoz N.M.,
RA Sze R.W., Grady W.M., Greenberg N.M., Ellenbogen R.G., Olson J.M.;
RT "Tumor paint: a chlorotoxin:Cy5.5 bioconjugate for intraoperative
RT visualization of cancer foci.";
RL Cancer Res. 67:6882-6888(2007).
RN [6]
RP BIOTECHNOLOGY.
RX PubMed=28403743; DOI=10.1177/1091581817697685;
RA Parrish-Novak J., Byrnes-Blake K., Lalayeva N., Burleson S., Fidel J.,
RA Gilmore R., Gayheart-Walsten P., Bricker G.A., Crumb W.J. Jr., Tarlo K.S.,
RA Hansen S., Wiss V., Malta E., Dernell W.S., Olson J.M., Miller D.M.;
RT "Nonclinical profile of BLZ-100, a tumor-targeting fluorescent imaging
RT agent.";
RL Int. J. Toxicol. 36:104-112(2017).
RN [7]
RP STRUCTURE BY NMR, AND DISULFIDE BONDS.
RX PubMed=7819188; DOI=10.1021/bi00001a003;
RA Lippens G., Najib J., Wodak S.J., Tartar A.;
RT "NMR sequential assignments and solution structure of chlorotoxin, a small
RT scorpion toxin that blocks chloride channels.";
RL Biochemistry 34:13-21(1995).
RN [8]
RP X-RAY CRYSTALLOGRAPHY (1.53 ANGSTROMS), SYNTHESIS, AND DISULFIDE BONDS.
RX PubMed=29483648; DOI=10.1038/s41594-018-0033-9;
RA Correnti C.E., Gewe M.M., Mehlin C., Bandaranayake A.D., Johnsen W.A.,
RA Rupert P.B., Brusniak M.Y., Clarke M., Burke S.E., De Van Der Schueren W.,
RA Pilat K., Turnbaugh S.M., May D., Watson A., Chan M.K., Bahl C.D.,
RA Olson J.M., Strong R.K.;
RT "Screening, large-scale production and structure-based classification of
RT cystine-dense peptides.";
RL Nat. Struct. Mol. Biol. 25:270-278(2018).
CC -!- FUNCTION: This toxin binds to the surface of glioma cells, and inhibits
CC their proliferation without having effects on normal brain cells. In
CC this context, this toxin has been described as a chloride channel
CC inhibitor (probably ClC-3/CLCN3) by causing its internalization via
CC caveolae (PubMed:16520829). It has also been described to selectively
CC interact with MMP2 (in complex with MT1-MMP (MMP14) and TIMP2), to
CC inhibit its enzymatic activity and to decrease its presence at the cell
CC surface (PubMed:12454020). {ECO:0000269|PubMed:12454020,
CC ECO:0000269|PubMed:16520829, ECO:0000269|PubMed:8383429}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:8383429}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland.
CC {ECO:0000305|PubMed:8383429}.
CC -!- DOMAIN: The presence of a 'disulfide through disulfide knot'
CC structurally defines this protein as a knottin.
CC {ECO:0000269|PubMed:7819188}.
CC -!- BIOTECHNOLOGY: Is under phase I clinical trial as BLZ-100 by Blaze
CC Bioscience Inc. as a fluorescent imaging agent that labels tumor tissue
CC to enable more complete and precise surgical resection. BLZ-100 is
CC composed of the chlorotoxin peptide covalently bound to the near-
CC infrared fluorophore indocyanine green. {ECO:0000269|PubMed:17638899,
CC ECO:0000269|PubMed:28403743}.
CC -!- MISCELLANEOUS: Does not interact with MMP-1, MMP-3 and MMP-9.
CC {ECO:0000305|PubMed:12454020}.
CC -!- MISCELLANEOUS: Was tested in clinical trial under the name TM-601 for
CC treatment of malignant glioma. {ECO:0000305|PubMed:16877732}.
CC -!- SIMILARITY: Belongs to the short scorpion toxin superfamily. Chloride
CC channel inhibitor family. {ECO:0000255|PROSITE-ProRule:PRU00545}.
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Chlorotoxin entry;
CC URL="https://en.wikipedia.org/wiki/Chlorotoxin";
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DR PIR; A48850; A48850.
DR PDB; 1CHL; NMR; -; A=1-36.
DR PDB; 5L1C; NMR; -; A=1-36.
DR PDB; 6ATW; X-ray; 1.53 A; A=1-36.
DR PDBsum; 1CHL; -.
DR PDBsum; 5L1C; -.
DR PDBsum; 6ATW; -.
DR AlphaFoldDB; P45639; -.
DR BMRB; P45639; -.
DR SMR; P45639; -.
DR EvolutionaryTrace; P45639; -.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0017081; F:chloride channel regulator activity; IEA:UniProtKB-KW.
DR GO; GO:0008191; F:metalloendopeptidase inhibitor activity; IEA:UniProtKB-KW.
DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
DR InterPro; IPR036574; Scorpion_toxin-like_sf.
DR InterPro; IPR007958; Scorpion_toxinS_Cl_inh.
DR Pfam; PF05294; Toxin_5; 1.
DR SUPFAM; SSF57095; SSF57095; 1.
DR PROSITE; PS51200; SHORT_SCORPION_CHLORIDE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Chloride channel impairing toxin; Direct protein sequencing;
KW Disulfide bond; Ion channel impairing toxin; Knottin;
KW Metalloenzyme inhibitor; Metalloprotease inhibitor; Neurotoxin;
KW Protease inhibitor; Secreted; Toxin;
KW Voltage-gated chloride channel impairing toxin.
FT PEPTIDE 1..36
FT /note="Chlorotoxin"
FT /evidence="ECO:0000269|PubMed:8383429"
FT /id="PRO_0000044941"
FT DISULFID 2..19
FT /evidence="ECO:0000269|PubMed:29483648,
FT ECO:0000269|PubMed:7819188, ECO:0000312|PDB:1CHL,
FT ECO:0000312|PDB:5L1C, ECO:0000312|PDB:6ATW"
FT DISULFID 5..28
FT /evidence="ECO:0000269|PubMed:29483648,
FT ECO:0000269|PubMed:7819188, ECO:0000312|PDB:1CHL,
FT ECO:0000312|PDB:5L1C, ECO:0000312|PDB:6ATW"
FT DISULFID 16..33
FT /evidence="ECO:0000269|PubMed:29483648,
FT ECO:0000269|PubMed:7819188, ECO:0000312|PDB:1CHL,
FT ECO:0000312|PDB:5L1C, ECO:0000312|PDB:6ATW"
FT DISULFID 20..35
FT /evidence="ECO:0000269|PubMed:29483648,
FT ECO:0000269|PubMed:7819188, ECO:0000312|PDB:1CHL,
FT ECO:0000312|PDB:5L1C, ECO:0000312|PDB:6ATW"
FT STRAND 2..4
FT /evidence="ECO:0007829|PDB:6ATW"
FT HELIX 12..20
FT /evidence="ECO:0007829|PDB:6ATW"
FT STRAND 22..25
FT /evidence="ECO:0007829|PDB:1CHL"
FT STRAND 26..29
FT /evidence="ECO:0007829|PDB:6ATW"
FT STRAND 32..35
FT /evidence="ECO:0007829|PDB:6ATW"
SQ SEQUENCE 36 AA; 4005 MW; 14A9F57559C6E92A CRC64;
MCMPCFTTDH QMARKCDDCC GGKGRGKCYG PQCLCR
