ID   TP1D_HADIN              Reviewed;          75 AA.
AC   P0DP48;
DT   07-JUN-2017, integrated into UniProtKB/Swiss-Prot.
DT   07-JUN-2017, sequence version 1.
DT   25-MAY-2022, entry version 9.
DE   RecName: Full=Pi-hexatoxin-Hi1d {ECO:0000303|PubMed:28320941};
DE            Short=Pi-HXTX-Hi1d {ECO:0000303|PubMed:28320941};
DE   AltName: Full=Double-knot toxin {ECO:0000305};
DE            Short=DkTx {ECO:0000305};
OS   Hadronyche infensa (Fraser island funnel-web spider) (Atrax infensus).
OC   Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Chelicerata; Arachnida; Araneae;
OC   Mygalomorphae; Hexathelidae; Hadronyche.
OX   NCBI_TaxID=153481;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   TISSUE=Venom gland;
RX   PubMed=28320941; DOI=10.1073/pnas.1614728114;
RA   Chassagnon I.R., McCarthy C.A., Chin Y.K., Pineda S.S., Keramidas A.,
RA   Mobli M., Pham V., De Silva T.M., Lynch J.W., Widdop R.E., Rash L.D.,
RA   King G.F.;
RT   "Potent neuroprotection after stroke afforded by a double-knot spider-venom
RT   peptide that inhibits acid-sensing ion channel 1a.";
RL   Proc. Natl. Acad. Sci. U.S.A. 114:3750-3755(2017).
CC   -!- FUNCTION: This toxin potently and selectively inhibits ASIC1a, an
CC       isoform of the gene ASIC1. It incompletely inhibits ASIC1a activation
CC       in a pH-independent and slowly reversible manner. This toxin acts by
CC       binding to and stabilizing the closed state of the channel, thereby
CC       impeding the transition into a conducting state. This toxin may bind to
CC       the acidic pocket of ASIC1a, since mutation of a key residue of this
CC       pocket (Arg-350) abolishes the ability of the toxin to inhibit ASIC1a.
CC       In vivo, this toxin protects the brain from neuronal injury when
CC       administered up to 8 hours after stroke onset.
CC       {ECO:0000250|UniProtKB:A0A1L1QJU3}.
CC   -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250|UniProtKB:P60514}.
CC   -!- TISSUE SPECIFICITY: Expressed by the venom gland.
CC       {ECO:0000305|PubMed:28320941}.
CC   -!- DOMAIN: The presence of a 'disulfide through disulfide knot'
CC       structurally defines this protein as a knottin. This toxin contains 2
CC       'disulfide through disulfide knots' that are separated by a short
CC       linker. {ECO:0000250|UniProtKB:A0A1L1QJU3}.
CC   -!- SIMILARITY: Belongs to the psalmotoxin-1 family. Double-knot toxin
CC       subfamily. {ECO:0000305}.
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DR   AlphaFoldDB; P0DP48; -.
DR   SMR; P0DP48; -.
DR   GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR   GO; GO:0099106; F:ion channel regulator activity; IEA:UniProtKB-KW.
DR   GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
PE   3: Inferred from homology;
KW   Disulfide bond; Ion channel impairing toxin;
KW   Proton-gated sodium channel impairing toxin; Secreted; Toxin.
FT   CHAIN           1..75
FT                   /note="Pi-hexatoxin-Hi1d"
FT                   /evidence="ECO:0000305|PubMed:28320941"
FT                   /id="PRO_0000440134"
FT   DISULFID        3..18
FT                   /evidence="ECO:0000250|UniProtKB:A0A1L1QJU3"
FT   DISULFID        10..23
FT                   /evidence="ECO:0000250|UniProtKB:A0A1L1QJU3"
FT   DISULFID        17..33
FT                   /evidence="ECO:0000250|UniProtKB:A0A1L1QJU3"
FT   DISULFID        40..55
FT                   /evidence="ECO:0000250|UniProtKB:A0A1L1QJU3"
FT   DISULFID        47..60
FT                   /evidence="ECO:0000250|UniProtKB:A0A1L1QJU3"
FT   DISULFID        54..71
FT                   /evidence="ECO:0000250|UniProtKB:A0A1L1QJU3"
SQ   SEQUENCE   75 AA;  8618 MW;  09556C6BD1B68328 CRC64;
     NECIRKWLSC VDRKNDCCEG LECYKRRHSF EVCVPIPGFC LVKWKQCDGR ERDCCAGLEC
     WKRSGNKSSV CAPIA