TXPR1_THRPR
ID TXPR1_THRPR Reviewed; 35 AA.
AC P83480;
DT 15-NOV-2002, integrated into UniProtKB/Swiss-Prot.
DT 15-NOV-2002, sequence version 1.
DT 25-MAY-2022, entry version 80.
DE RecName: Full=Beta/omega-theraphotoxin-Tp1a {ECO:0000305};
DE Short=Beta/omega-TRTX-Tp1a {ECO:0000305};
DE AltName: Full=Protoxin-1 {ECO:0000305};
DE Short=ProTx-1 {ECO:0000305};
DE Short=ProTx1 {ECO:0000305};
DE AltName: Full=Protoxin-I {ECO:0000303|PubMed:24530065, ECO:0000303|PubMed:24886690};
DE Short=ProTx-I {ECO:0000303|PubMed:12475222, ECO:0000303|PubMed:17087985, ECO:0000303|PubMed:20351484, ECO:0000303|PubMed:24530065, ECO:0000303|PubMed:24886690, ECO:0000303|PubMed:26843868, ECO:0000303|PubMed:29703751};
OS Thrixopelma pruriens (Peruvian green velvet tarantula).
OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Chelicerata; Arachnida; Araneae;
OC Mygalomorphae; Theraphosidae; Thrixopelma.
OX NCBI_TaxID=213387;
RN [1]
RP PROTEIN SEQUENCE, SYNTHESIS, FUNCTION, SUBCELLULAR LOCATION, AND MASS
RP SPECTROMETRY.
RC TISSUE=Venom;
RX PubMed=12475222; DOI=10.1021/bi026546a;
RA Middleton R.E., Warren V.A., Kraus R.L., Hwang J.C., Liu C.J., Dai G.,
RA Brochu R.M., Kohler M.G., Gao Y.-D., Garsky V.M., Bogusky M.J., Mehl J.T.,
RA Cohen C.J., Smith M.M.;
RT "Two tarantula peptides inhibit activation of multiple sodium channels.";
RL Biochemistry 41:14734-14747(2002).
RN [2]
RP SYNTHESIS, AND FUNCTION.
RX PubMed=17087985; DOI=10.1016/j.toxicon.2006.09.014;
RA Priest B.T., Blumenthal K.M., Smith J.J., Warren V.A., Smith M.M.;
RT "ProTx-I and ProTx-II: gating modifiers of voltage-gated sodium channels.";
RL Toxicon 49:194-201(2007).
RN [3]
RP FUNCTION.
RX PubMed=20351484; DOI=10.1254/jphs.09356fp;
RA Ohkubo T., Yamazaki J., Kitamura K.;
RT "Tarantula toxin ProTx-I differentiates between human T-type voltage-gated
RT Ca2+ Channels Cav3.1 and Cav3.2.";
RL J. Pharmacol. Sci. 112:452-458(2010).
RN [4]
RP FUNCTION.
RX PubMed=24886690; DOI=10.1186/1756-6606-7-36;
RA Bladen C., Hamid J., Souza I.A., Zamponi G.W.;
RT "Block of T-type calcium channels by protoxins I and II.";
RL Mol. Brain 7:36-36(2014).
RN [5]
RP DOMAIN.
RX PubMed=26843868; DOI=10.1155/2015/537508;
RA Kikuchi K., Sugiura M., Kimura T.;
RT "High proteolytic resistance of spider-derived inhibitor cystine knots.";
RL Int. J. Pept. 2015:537508-537508(2015).
RN [6]
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).
RN [7]
RP FUNCTION ON NAV1.7/SCN9A, AND SYNTHESIS.
RX PubMed=31234412; DOI=10.3390/toxins11060367;
RA Nicolas S., Zoukimian C., Bosmans F., Montnach J., Diochot S., Cuypers E.,
RA De Waard S., Beroud R., Mebs D., Craik D., Boturyn D., Lazdunski M.,
RA Tytgat J., De Waard M.;
RT "Chemical synthesis, proper folding, Nav channel selectivity profile and
RT analgesic properties of the spider peptide Phlotoxin 1.";
RL Toxins 11:0-0(2019).
RN [8]
RP RECOMBINANT EXPRESSION, FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF
RP LEU-6; LYS-17; LEU-19; TRP-27; VAL-29; TRP-30 AND ASP-31.
RX PubMed=32511987; DOI=10.1016/j.bcp.2020.114080;
RA Rupasinghe D.B., Herzig V., Vetter I., Dekan Z., Gilchrist J., Bosmans F.,
RA Alewood P.F., Lewis R.J., King G.F.;
RT "Mutational analysis of ProTx-I and the novel venom peptide Pe1b provide
RT insight into residues responsible for selective inhibition of the analgesic
RT drug target NaV1.7.";
RL Biochem. Pharmacol. 181:114080-114080(2020).
RN [9] {ECO:0007744|PDB:2M9L}
RP STRUCTURE BY NMR, DISULFIDE BONDS, FUNCTION, AND MUTAGENESIS OF ARG-3;
RP TRP-5; GLN-13; LEU-19; SER-22; ARG-23; TRP-27; VAL-29; TRP-30; ASP-31;
RP GLY-32; PHE-34 AND SER-35.
RX PubMed=24530065; DOI=10.1016/j.cub.2014.01.013;
RA Gui J., Liu B., Cao G., Lipchik A.M., Perez M., Dekan Z., Mobli M.,
RA Daly N.L., Alewood P.F., Parker L.L., King G.F., Zhou Y., Jordt S.E.,
RA Nitabach M.N.;
RT "A tarantula-venom peptide antagonizes the TRPA1 nociceptor ion channel by
RT binding to the S1-S4 gating domain.";
RL Curr. Biol. 24:473-483(2014).
CC -!- FUNCTION: Ion channel impairing toxin that inhibits voltage-gated
CC calcium channel Cav3.1/CACNA1G (IC(50)=53 nM), voltage-gated potassium
CC channels Kv2.1/KCNB1 (IC(50)=411 nM), all sodium channels tested
CC (Nav1.2/SCN2A (IC(50)=60-104 nM), Nav1.5/SCN5A (IC(50)=76-358 nM),
CC Nav1.6/SCN8A (IC(50)=21-133 nM), Nav1.7/SCN9A (IC(50)=51-95 nM), and
CC Nav1.8/SCN10A) and the nociceptor cation channel TRPA1 (IC(50)=389 nM)
CC (PubMed:12475222, PubMed:17087985, PubMed:20351484, PubMed:24886690,
CC PubMed:29703751, PubMed:31234412, PubMed:24530065). Acts as a potent
CC and selective blocker of voltage-gated calcium channel Cav3.1/CACNA1G,
CC but not of Cav3.2/CACNA1H, and Cav3.3/CACNA1I (PubMed:20351484,
CC PubMed:24886690). On Nav1.7/SCN9A, primarily interacts with the DII and
CC DIV voltage-sensor domains (PubMed:32511987). Also acts as an inhibitor
CC of nociceptor cation channel TRPA1 (IC(50)~389 nM) by binding to the
CC S1-S4 gating domain of TRPA1 (PubMed:24530065). It shows moderate
CC affinity for lipid bilayers (PubMed:29703751).
CC {ECO:0000269|PubMed:12475222, ECO:0000269|PubMed:17087985,
CC ECO:0000269|PubMed:20351484, ECO:0000269|PubMed:24530065,
CC ECO:0000269|PubMed:24886690, ECO:0000269|PubMed:29703751,
CC ECO:0000269|PubMed:31234412}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:12475222}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland.
CC {ECO:0000305|PubMed:12475222}.
CC -!- DOMAIN: The presence of a 'disulfide through disulfide knot'
CC structurally defines this protein as a knottin.
CC {ECO:0000269|PubMed:24530065}.
CC -!- PTM: An unnatural amidation at Ser-35 provokes a 14-fold increased
CC toxin ability to inhibit Nav1.2/SCN2A and a ~2-fold decreased toxin
CC ability to inhibit both Nav1.5/SCN5A and Nav1.6/SCN8A.
CC {ECO:0000269|PubMed:32511987}.
CC -!- MASS SPECTROMETRY: Mass=3988.3; Method=Electrospray;
CC Evidence={ECO:0000269|PubMed:12475222};
CC -!- PHARMACEUTICAL: The amidated mutant G32A (ProTx-I-G32A-NH2) shows a
CC decreased ability to inhibit all sodium channels tested, with a more
CC pronounced reduction on Nav1.2/SCN2A and Nav1.5/SCN5A. As a
CC consequence, this mutant shows an enhanced selectivity and potency for
CC Nav1.7/SCN9A, and thus may provide a good starting point for second
CC generation analogs to treat pain. {ECO:0000305|PubMed:32511987}.
CC -!- MISCELLANEOUS: The primary structure of the mature peptide is identical
CC to that of Beta/omega-theraphotoxin-Bp1a from Bumba pulcherrimaklaasi
CC (AC P0DQN3). {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the neurotoxin 10 (Hwtx-1) family. 54 (ProTx-1)
CC subfamily. {ECO:0000305}.
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DR PDB; 2M9L; NMR; -; A=1-35.
DR PDBsum; 2M9L; -.
DR AlphaFoldDB; P83480; -.
DR BMRB; P83480; -.
DR SMR; P83480; -.
DR TCDB; 8.B.5.1.1; the na(+)/k(+)/ca(2+) channel targeting tarantula huwentoxin (tht) family.
DR ArachnoServer; AS000413; beta/omega-theraphotoxin-Tp1a.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0019855; F:calcium channel inhibitor activity; IDA:UniProtKB.
DR GO; GO:0015459; F:potassium channel regulator activity; IEA:UniProtKB-KW.
DR GO; GO:0017080; F:sodium channel regulator activity; IEA:UniProtKB-KW.
DR GO; GO:0090729; F:toxin activity; IDA:UniProtKB.
DR InterPro; IPR011696; Huwentoxin-1.
DR Pfam; PF07740; Toxin_12; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Calcium channel impairing toxin; Direct protein sequencing;
KW Disulfide bond; Ion channel impairing toxin; Knottin; Neurotoxin;
KW Pharmaceutical; Potassium channel impairing toxin; Secreted; Toxin;
KW Voltage-gated calcium channel impairing toxin;
KW Voltage-gated potassium channel impairing toxin;
KW Voltage-gated sodium channel impairing toxin.
FT PEPTIDE 1..35
FT /note="Beta/omega-theraphotoxin-Tp1a"
FT /evidence="ECO:0000303|PubMed:12475222"
FT /id="PRO_0000045029"
FT SITE 6
FT /note="Pharmacophore for Nav1.7/SCN9A"
FT /evidence="ECO:0000269|PubMed:32511987"
FT SITE 19
FT /note="Pharmacophore for Nav1.7/SCN9A"
FT /evidence="ECO:0000269|PubMed:32511987"
FT SITE 27
FT /note="Pharmacophore for Nav1.7/SCN9A"
FT /evidence="ECO:0000269|PubMed:32511987"
FT SITE 29
FT /note="Pharmacophore for Nav1.7/SCN9A"
FT /evidence="ECO:0000269|PubMed:32511987"
FT SITE 30
FT /note="Pharmacophore for Nav1.7/SCN9A"
FT /evidence="ECO:0000269|PubMed:32511987"
FT SITE 31
FT /note="Pharmacophore for Nav1.7/SCN9A"
FT /evidence="ECO:0000269|PubMed:32511987"
FT DISULFID 2..16
FT /evidence="ECO:0000269|PubMed:24530065,
FT ECO:0007744|PDB:2M9L"
FT DISULFID 9..21
FT /evidence="ECO:0000269|PubMed:24530065,
FT ECO:0007744|PDB:2M9L"
FT DISULFID 15..28
FT /evidence="ECO:0000269|PubMed:24530065,
FT ECO:0007744|PDB:2M9L"
FT MUTAGEN 3
FT /note="R->A: Reduced ability to inhibit sodium channel
FT Nav1.2/SCN2A."
FT /evidence="ECO:0000269|PubMed:24530065"
FT MUTAGEN 5
FT /note="W->A: Reduced ability to inhibit sodium channel
FT Nav1.2/SCN2A."
FT /evidence="ECO:0000269|PubMed:24530065"
FT MUTAGEN 6
FT /note="L->A: Decrease in ability to inhibit Nav1.7/SCN9A."
FT /evidence="ECO:0000269|PubMed:32511987"
FT MUTAGEN 13
FT /note="Q->A: Reduced ability to inhibit nociceptor cation
FT channel TRPA1."
FT /evidence="ECO:0000269|PubMed:24530065"
FT MUTAGEN 17
FT /note="K->E: Decrease in ability to inhibit Nav1.2/SCN2A,
FT Nav1.5/SCN5A, Nav1.6/SCN8A and Nav1.7/SCN9A."
FT /evidence="ECO:0000269|PubMed:32511987"
FT MUTAGEN 19
FT /note="L->A: Decrease in ability to inhibit the channels
FT TRPA1, Nav1.2/SCN2A, and Nav1.7/SCN9A, probably due to
FT improper folding."
FT /evidence="ECO:0000269|PubMed:24530065,
FT ECO:0000269|PubMed:32511987"
FT MUTAGEN 22
FT /note="S->A: Reduced ability to inhibit nociceptor cation
FT channel TRPA1. Reduced ability to inhibit sodium channel
FT Nav1.2/SCN2A."
FT /evidence="ECO:0000269|PubMed:24530065"
FT MUTAGEN 23
FT /note="R->A: Reduced ability to inhibit sodium channel
FT Nav1.2/SCN2A."
FT /evidence="ECO:0000269|PubMed:24530065"
FT MUTAGEN 27
FT /note="W->A: Decrease in ability to inhibit Nav1.2/SCN2A
FT and Nav1.7/SCN9A."
FT /evidence="ECO:0000269|PubMed:24530065,
FT ECO:0000269|PubMed:32511987"
FT MUTAGEN 29
FT /note="V->A: Decrease in ability to inhibit Nav1.2/SCN2A
FT and Nav1.7/SCN9A."
FT /evidence="ECO:0000269|PubMed:24530065,
FT ECO:0000269|PubMed:32511987"
FT MUTAGEN 30
FT /note="W->A: Decrease in ability to inhibit the channels
FT TRPA1, Nav1.2/SCN2A and Nav1.7/SCN9A."
FT /evidence="ECO:0000269|PubMed:24530065,
FT ECO:0000269|PubMed:32511987"
FT MUTAGEN 31
FT /note="D->A: Decrease in ability to inhibit Nav1.2/SCN2A
FT and Nav1.7/SCN9A."
FT /evidence="ECO:0000269|PubMed:24530065,
FT ECO:0000269|PubMed:32511987"
FT MUTAGEN 32
FT /note="G->A: Reduced ability to inhibit sodium channel
FT Nav1.2/SCN2A."
FT /evidence="ECO:0000269|PubMed:24530065"
FT MUTAGEN 34
FT /note="F->A: Reduced ability to inhibit nociceptor cation
FT channel TRPA1. Reduced ability to inhibit sodium channel
FT Nav1.2/SCN2A."
FT /evidence="ECO:0000269|PubMed:24530065"
FT MUTAGEN 35
FT /note="S->A: Reduced ability to inhibit nociceptor cation
FT channel TRPA1."
FT /evidence="ECO:0000269|PubMed:24530065"
FT STRAND 19..22
FT /evidence="ECO:0007829|PDB:2M9L"
FT TURN 23..26
FT /evidence="ECO:0007829|PDB:2M9L"
FT STRAND 27..30
FT /evidence="ECO:0007829|PDB:2M9L"
FT TURN 31..33
FT /evidence="ECO:0007829|PDB:2M9L"
SQ SEQUENCE 35 AA; 3994 MW; 13F35B2F3A59B2A5 CRC64;
ECRYWLGGCS AGQTCCKHLV CSRRHGWCVW DGTFS
