TX1B_HETMC
ID TX1B_HETMC Reviewed; 34 AA.
AC P0DOC5;
DT 05-OCT-2016, integrated into UniProtKB/Swiss-Prot.
DT 05-OCT-2016, sequence version 1.
DT 25-MAY-2022, entry version 16.
DE RecName: Full=Delta-theraphotoxin-Hm1b {ECO:0000303|PubMed:27281198};
DE Short=Delta-TRTX-Hm1b {ECO:0000305|PubMed:27281198};
OS Heteroscodra maculata (Togo starburst tarantula) (Togo starburst baboon
OS spider).
OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Chelicerata; Arachnida; Araneae;
OC Mygalomorphae; Theraphosidae; Heteroscodra.
OX NCBI_TaxID=268413;
RN [1]
RP PROTEIN SEQUENCE, FUNCTION, SUBCELLULAR LOCATION, MASS SPECTROMETRY,
RP AMIDATION AT PHE-34, AND BIOASSAY.
RC TISSUE=Venom;
RX PubMed=27281198; DOI=10.1038/nature17976;
RA Osteen J.D., Herzig V., Gilchrist J., Emrick J.J., Zhang C., Wang X.,
RA Castro J., Garcia-Caraballo S., Grundy L., Rychkov G.Y., Weyer A.D.,
RA Dekan Z., Undheim E.A., Alewood P., Stucky C.L., Brierley S.M.,
RA Basbaum A.I., Bosmans F., King G.F., Julius D.;
RT "Selective spider toxins reveal a role for the Nav1.1 channel in mechanical
RT pain.";
RL Nature 534:494-499(2016).
RN [2]
RP STRUCTURE BY NMR, DISULFIDE BOND, MASS SPECTROMETRY, PHARMACEUTICAL,
RP STABILITY IN CEREBROSPINAL FLUID AND SERUM, RECOMBINANT EXPRESSION, AND
RP AMIDATION AT PHE-34.
RC TISSUE=Venom;
RX PubMed=32335140; DOI=10.1016/j.bcp.2020.113991;
RA Chow C.Y., Chin Y.K.Y., Ma L., Undheim E.A.B., Herzig V., King G.F.;
RT "A selective Nav1.1 activator with potential for treatment of Dravet
RT syndrome epilepsy.";
RL Biochem. Pharmacol. 181:113991-113991(2020).
CC -!- FUNCTION: Gating-modifier toxin that potently and selectively acts on
CC Nav1.1/SCN1A and Nav1.3/SCN3A (PubMed:32335140). It enhances
CC hNav1.1/SCN1A currents and delays fast inactivation of the channel
CC (EC(50)=11.6 nM), leading to a sustained current (PubMed:32335140).
CC Similar effects are observed at Nav1.3/SCN3A (EC(50)=11.8 nM), but with
CC less sustained currents (PubMed:32335140). When tested on Nav1.2/SCN2A,
CC the native toxin decreases the peak current by 50% at saturating
CC concentration, whereas the recombinant toxin only shows a weak decrease
CC of peak current (PubMed:32335140). The native toxin specifically
CC activates the voltage-gated sodium channel Nav1.1/SCN1A in
CC somatosensory neurons to elicit acute pain and mechanical allodynia
CC (PubMed:27281198). When tested on Nav1.1/SCN1A, the toxin induces a
CC hyperpolarising shift of the voltage-dependence of steady-state
CC activation, and induces a depolarizing shift in the voltage dependence
CC of inactivation (PubMed:32335140). In addition, it does not modify the
CC recovery from fast inactivation in Nav1.1/SCN1A (PubMed:32335140). The
CC toxin hydrophobic face probably interacts with the domain IV voltage-
CC sensor of Nav1.1/SCN1A and Nav1.3/SCN3A and may trap the voltage-
CC sensing S4 helix in a partially activated state (PubMed:32335140). In
CC vivo, intracerebroventricular injection into mice elicits convulsions,
CC spasms, tremors and rapid death (By similarity). When injected into
CC mouse hindpaw, the toxin elicits an immediate and robust response to
CC pain (PubMed:27281198). However, intraplantar injection of toxin does
CC not cause neurogenic inflammation or alter sensitivity to heat,
CC indicative of a modality-specific effect on mechanosensitive neurons
CC (PubMed:27281198). {ECO:0000250|UniProtKB:P60992,
CC ECO:0000269|PubMed:27281198, ECO:0000269|PubMed:32335140}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:27281198}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland.
CC {ECO:0000305|PubMed:27281198}.
CC -!- DOMAIN: The presence of a 'disulfide through disulfide knot'
CC structurally defines this protein as a knottin.
CC {ECO:0000269|PubMed:32335140}.
CC -!- MASS SPECTROMETRY: Mass=3892.60; Method=MALDI;
CC Evidence={ECO:0000269|PubMed:27281198};
CC -!- MASS SPECTROMETRY: Mass=3892.23; Method=MALDI; Note=Monoisotopic mass.;
CC Evidence={ECO:0000269|PubMed:32335140};
CC -!- PHARMACEUTICAL: May be used to develop new agents to treat
CC Nav1.1/SCN1A-associated epilepsies, such as the Dravet syndrome.
CC {ECO:0000305|PubMed:32335140}.
CC -!- MISCELLANEOUS: Shows high stability in both cerebrospinal fluid and
CC human serum (PubMed:32335140). Half-life of the recombinant toxin is
CC >40 hours in human serum, and >70 hours in human cerebrospinal fluid
CC (PubMed:32335140). {ECO:0000269|PubMed:32335140}.
CC -!- MISCELLANEOUS: Does not inhibit Nav1.4/SCN4A, Nav1.5/SCN5A,
CC Nav1.6/SCN8A, and Nav1.7/SCN9A sodium channels.
CC {ECO:0000269|PubMed:32335140}.
CC -!- SIMILARITY: Belongs to the neurotoxin 10 (Hwtx-1) family. 09 (HaTx)
CC subfamily. {ECO:0000305}.
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DR PDB; 6V6T; NMR; -; A=1-34.
DR PDBsum; 6V6T; -.
DR AlphaFoldDB; P0DOC5; -.
DR BMRB; P0DOC5; -.
DR SMR; P0DOC5; -.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0008200; F:ion channel inhibitor activity; IEA:InterPro.
DR GO; GO:0017080; F:sodium channel regulator activity; IDA:UniProtKB.
DR GO; GO:0090729; F:toxin activity; IDA:UniProtKB.
DR GO; GO:0044488; P:modulation of voltage-gated sodium channel activity in another organism; IDA:UniProtKB.
DR InterPro; IPR011696; Huwentoxin-1.
DR Pfam; PF07740; Toxin_12; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Amidation; Direct protein sequencing; Disulfide bond;
KW Ion channel impairing toxin; Knottin; Neurotoxin; Pharmaceutical; Secreted;
KW Toxin; Voltage-gated sodium channel impairing toxin.
FT CHAIN 1..34
FT /note="Delta-theraphotoxin-Hm1b"
FT /evidence="ECO:0000269|PubMed:27281198"
FT /id="PRO_0000437537"
FT MOD_RES 34
FT /note="Phenylalanine amide"
FT /evidence="ECO:0000269|PubMed:27281198,
FT ECO:0000269|PubMed:32335140"
FT DISULFID 2..16
FT /evidence="ECO:0000269|PubMed:32335140,
FT ECO:0007744|PDB:6V6T"
FT DISULFID 9..21
FT /evidence="ECO:0000269|PubMed:32335140,
FT ECO:0007744|PDB:6V6T"
FT DISULFID 15..28
FT /evidence="ECO:0000269|PubMed:32335140,
FT ECO:0007744|PDB:6V6T"
FT HELIX 12..14
FT /evidence="ECO:0007829|PDB:6V6T"
FT TURN 23..25
FT /evidence="ECO:0007829|PDB:6V6T"
SQ SEQUENCE 34 AA; 3901 MW; 277CB0F3D1F8133A CRC64;
ECRYLFGGCK TTADCCKHLG CRTDLYYCAW DGTF
