TX1_CERMR
ID TX1_CERMR Reviewed; 33 AA.
AC P84507;
DT 25-OCT-2005, integrated into UniProtKB/Swiss-Prot.
DT 25-OCT-2005, sequence version 1.
DT 25-MAY-2022, entry version 63.
DE RecName: Full=Beta-theraphotoxin-Cm1a {ECO:0000305};
DE Short=Beta-TRTX-Cm1a {ECO:0000305};
DE AltName: Full=CcoTx-I {ECO:0000303|PubMed:29703751};
DE AltName: Full=Ceratotoxin-1 {ECO:0000303|PubMed:16267209, ECO:0000303|PubMed:27129258};
DE Short=CcoTx1 {ECO:0000303|PubMed:16267209, ECO:0000303|PubMed:27129258};
OS Ceratogyrus marshalli (Straighthorned baboon tarantula) (Ceratogyrus
OS cornuatus).
OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Chelicerata; Arachnida; Araneae;
OC Mygalomorphae; Theraphosidae; Ceratogyrus.
OX NCBI_TaxID=316287;
RN [1]
RP PROTEIN SEQUENCE, FUNCTION, BIOASSAY, SUBCELLULAR LOCATION, MASS
RP SPECTROMETRY, AND AMIDATION AT LEU-33.
RC TISSUE=Venom;
RX PubMed=16267209; DOI=10.1124/mol.105.015941;
RA Bosmans F., Rash L., Zhu S., Diochot S., Lazdunski M., Escoubas P.,
RA Tytgat J.;
RT "Four novel tarantula toxins as selective modulators of voltage-gated
RT sodium channel subtypes.";
RL Mol. Pharmacol. 69:419-429(2006).
RN [2]
RP FUNCTION, MUTAGENESIS OF TRP-5; LYS-12; LYS-18; 19-ASN--THR-21; ARG-24;
RP 25-ARG-ASP-26 AND 31-TYR-ASP-32, X-RAY CRYSTALLOGRAPHY (1.75 ANGSTROMS) OF
RP MUTANT 2670 IN COMPLEX WITH AN ANTIBODY FRAGMENT, AND PHARMACEUTICAL.
RX PubMed=27129258; DOI=10.1074/jbc.m116.725978;
RA Shcherbatko A., Rossi A., Foletti D., Zhu G., Bogin O., Galindo Casas M.,
RA Rickert M., Hasa-Moreno A., Bartsevich V., Crameri A., Steiner A.R.,
RA Henningsen R., Gill A., Pons J., Shelton D.L., Rajpal A., Strop P.;
RT "Engineering highly potent and selective microproteins against Nav1.7
RT sodium channel for treatment of pain.";
RL J. Biol. Chem. 291:13974-13986(2016).
RN [3]
RP FUNCTION.
RX PubMed=28880874; DOI=10.1371/journal.pone.0182848;
RA Sousa S.R., Wingerd J.S., Brust A., Bladen C., Ragnarsson L., Herzig V.,
RA Deuis J.R., Dutertre S., Vetter I., Zamponi G.W., King G.F., Alewood P.F.,
RA Lewis R.J.;
RT "Discovery and mode of action of a novel analgesic beta-toxin from the
RT African spider Ceratogyrus darlingi.";
RL PLoS ONE 12:E0182848-E0182848(2017).
RN [4]
RP FUNCTION, AND SYNTHESIS.
RX PubMed=29703751; DOI=10.1074/jbc.ra118.002553;
RA Agwa A.J., Peigneur S., Chow C.Y., Lawrence N., Craik D.J., Tytgat J.,
RA King G.F., Henriques S.T., Schroeder C.I.;
RT "Gating modifier toxins isolated from spider venom: modulation of voltage-
RT gated sodium channels and the role of lipid membranes.";
RL J. Biol. Chem. 293:9041-9052(2018).
CC -!- FUNCTION: Inhibits many voltage-gated sodium channels and one voltage-
CC gated calcium channel (Cav2.2/CACNA1B (IC(50)=400 nM), Nav1.2/SCN2A
CC (IC(50)=3-70 nM), Nav1.1/SCN1A (IC(50)=523-1060 nM), Nav1.7/SCN9A
CC (IC(50)=129.1-5120 nM), Nav1.4/SCN4A (IC(50)=263-888 nM or >10 uM) and
CC Nav1.5/SCN5A (IC(50)=188-323 nM or >10 uM)) (PubMed:16267209,
CC PubMed:27129258, PubMed:28880874, PubMed:29703751). It acts by shifting
CC the voltage dependence of channel activation to more depolarized
CC potentials and by blocking the inward component of the sodium current
CC (PubMed:16267209). It shows moderate affinity for lipid bilayers
CC (PubMed:29703751). On Nav1.7/SCN9A, it has been shown to interact with
CC the S3-S4 loop of domain DII (site 4) (PubMed:27129258). Is
CC significantly more potent against Nav1.2/SCN2A than the other Nav
CC channel subtypes (PubMed:16267209). In vivo, this toxin causes general
CC ataxia, lack of response to stimuli, and semiparalysis
CC (PubMed:16267209). After a few minutes, the mice are unable to stand,
CC and breathing is reduced in rhythm and intensity (PubMed:16267209).
CC Symptoms gradually increase with progressive slowing of breathing and
CC flaccid paralysis, death occurred within 10 to 20 minutes post
CC injection (PubMed:16267209). Animals remain totally flaccid, and no
CC symptoms of excitatory neurotoxicity are observed (PubMed:16267209).
CC {ECO:0000269|PubMed:16267209, ECO:0000269|PubMed:27129258,
CC ECO:0000269|PubMed:28880874, ECO:0000269|PubMed:29703751}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:16267209}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland.
CC {ECO:0000305|PubMed:16267209}.
CC -!- DOMAIN: The presence of a 'disulfide through disulfide knot'
CC structurally defines this protein as a knottin.
CC {ECO:0000305|PubMed:27129258}.
CC -!- MASS SPECTROMETRY: Mass=4041.79; Method=MALDI;
CC Evidence={ECO:0000269|PubMed:16267209};
CC -!- PHARMACEUTICAL: Derivatives such as D1Z/M5I/K18Y/R24Ka or D1Z/M5I/R27Na
CC are under preclinical trial by Pfizer to treat pain.
CC {ECO:0000305|PubMed:27129258}.
CC -!- MISCELLANEOUS: Synthetic variant D1Z/M5I/K18Y/R24Ka has a N-terminal
CC pyroglutamate and a C-terminal amidation. It shows an IC(50)=2.7 nM on
CC Nav1.7/SCN9A and IC(50)>3 uM on Nav1.4/SCN4A and Nav1.5/SCN5A.
CC {ECO:0000269|PubMed:27129258}.
CC -!- MISCELLANEOUS: Synthetic variant D1Z/M5I/R27Na has a N-terminal
CC pyroglutamate and a C-terminal amidation. It shows an IC(50)=2.8 nM on
CC Nav1.7/SCN9A and IC(50)>3 uM on Nav1.4/SCN4A and Nav1.5/SCN5A.
CC {ECO:0000269|PubMed:27129258}.
CC -!- MISCELLANEOUS: Does not inhibit Cav1.3/CACNA1D and Cav3.1/CACNA1G
CC (PubMed:28880874). Does not inhibit Nav1.3/SCN3A, Nav1.6/SCN8A,
CC Nav1.8/SCN10A (PubMed:16267209, PubMed:28880874).
CC {ECO:0000269|PubMed:16267209, ECO:0000269|PubMed:28880874}.
CC -!- SIMILARITY: Belongs to the neurotoxin 10 (Hwtx-1) family. 04 (CcoTx1)
CC subfamily. {ECO:0000305}.
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DR PDB; 5EPM; X-ray; 1.75 A; C/D=1-33.
DR PDB; 6BR0; NMR; -; A=1-33.
DR PDBsum; 5EPM; -.
DR PDBsum; 6BR0; -.
DR AlphaFoldDB; P84507; -.
DR BMRB; P84507; -.
DR SMR; P84507; -.
DR ABCD; P84507; 1 sequenced antibody.
DR ArachnoServer; AS000221; beta-theraphotoxin-Cm1a.
DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB.
DR GO; GO:0005246; F:calcium channel regulator activity; IEA:UniProtKB-KW.
DR GO; GO:0019871; F:sodium channel inhibitor activity; IDA:UniProtKB.
DR GO; GO:0090729; F:toxin activity; IDA:UniProtKB.
DR GO; GO:0044489; P:negative regulation of voltage-gated sodium channel activity in another organism; IDA:UniProtKB.
DR InterPro; IPR011696; Huwentoxin-1.
DR InterPro; IPR013140; Huwentoxin_CS1.
DR Pfam; PF07740; Toxin_12; 1.
DR PROSITE; PS60021; HWTX_1; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Amidation; Calcium channel impairing toxin;
KW Direct protein sequencing; Disulfide bond; Ion channel impairing toxin;
KW Knottin; Neurotoxin; Pharmaceutical; Secreted; Toxin;
KW Voltage-gated calcium channel impairing toxin;
KW Voltage-gated sodium channel impairing toxin.
FT PEPTIDE 1..33
FT /note="Beta-theraphotoxin-Cm1a"
FT /evidence="ECO:0000269|PubMed:16267209"
FT /id="PRO_0000045000"
FT MOD_RES 33
FT /note="Leucine amide"
FT /evidence="ECO:0000269|PubMed:16267209"
FT DISULFID 2..17
FT /evidence="ECO:0000305|PubMed:27129258"
FT DISULFID 9..22
FT /evidence="ECO:0000305|PubMed:27129258"
FT DISULFID 16..29
FT /evidence="ECO:0000305|PubMed:27129258"
FT MUTAGEN 5
FT /note="W->I: Important increase in potency toward
FT Nav1.7/SCN9A, and low potency on Nav1.4/SCN4A and
FT Nav1.5/SCN5A; synthetic variant D1Z/M5I/K18Y/R24Ka and
FT synthetic variant D1Z/M5I/R27Na."
FT /evidence="ECO:0000269|PubMed:27129258"
FT MUTAGEN 12
FT /note="K->E: Important increase in potency toward
FT Nav1.7/SCN9A, and low potency on Nav1.4/SCN4A and
FT Nav1.5/SCN5A; synthetic variant D1Z/M5I/K18Y/R24Ka and
FT synthetic variant D1Z/M5I/R27Na."
FT /evidence="ECO:0000269|PubMed:27129258"
FT MUTAGEN 18
FT /note="K->Y: Important increase in potency toward
FT Nav1.7/SCN9A, and low potency on Nav1.4/SCN4A and
FT Nav1.5/SCN5A; synthetic variant D1Z/M5I/K18Y/R24Ka."
FT /evidence="ECO:0000269|PubMed:27129258"
FT MUTAGEN 19..21
FT /note="NYT->RLV: Important increase in potency toward
FT Nav1.7/SCN9A, and low potency on Nav1.4/SCN4A and
FT Nav1.5/SCN5A; synthetic variant D1Z/M5I/K18Y/R24Ka and
FT synthetic variant D1Z/M5I/R27Na."
FT /evidence="ECO:0000269|PubMed:27129258"
FT MUTAGEN 24
FT /note="R->K: Important increase in potency toward
FT Nav1.7/SCN9A, and low potency on Nav1.4/SCN4A and
FT Nav1.5/SCN5A; synthetic variant D1Z/M5I/K18Y/R24Ka."
FT /evidence="ECO:0000269|PubMed:27129258"
FT MUTAGEN 25..26
FT /note="RD->SH: Important increase in potency toward
FT Nav1.7/SCN9A, and low potency on Nav1.4/SCN4A and
FT Nav1.5/SCN5A; synthetic variant D1Z/M5I/K18Y/R24Ka and
FT synthetic variant D1Z/M5I/R27Na."
FT /evidence="ECO:0000269|PubMed:27129258"
FT MUTAGEN 27
FT /note="R->N: Important increase in potency toward
FT Nav1.7/SCN9A, and low potency on Nav1.4/SCN4A and
FT Nav1.5/SCN5A; synthetic variant D1Z/M5I/R27Na."
FT /evidence="ECO:0000269|PubMed:27129258"
FT MUTAGEN 31..32
FT /note="YD->WK: Important increase in potency toward
FT Nav1.7/SCN9A, and low potency on Nav1.4/SCN4A and
FT Nav1.5/SCN5A; synthetic variant D1Z/M5I/K18Y/R24Ka and
FT synthetic variant D1Z/M5I/R27Na."
FT /evidence="ECO:0000269|PubMed:27129258"
FT HELIX 11..13
FT /evidence="ECO:0007829|PDB:5EPM"
FT STRAND 20..22
FT /evidence="ECO:0007829|PDB:5EPM"
FT TURN 24..26
FT /evidence="ECO:0007829|PDB:5EPM"
FT STRAND 28..31
FT /evidence="ECO:0007829|PDB:5EPM"
SQ SEQUENCE 33 AA; 4052 MW; 2DED2300E19FFF1A CRC64;
DCLGWFKSCD PKNDKCCKNY TCSRRDRWCK YDL
