PN3A_PAMNI
ID PN3A_PAMNI Reviewed; 35 AA.
AC P0DM12;
DT 23-MAY-2018, integrated into UniProtKB/Swiss-Prot.
DT 23-MAY-2018, sequence version 1.
DT 25-MAY-2022, entry version 11.
DE RecName: Full=Mu-theraphotoxin-Pn3a {ECO:0000303|PubMed:28106092};
DE Short=Mu-TRTX-Pn3a {ECO:0000303|PubMed:28106092};
OS Pamphobeteus nigricolor (Giant blue bloom tarantula).
OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Chelicerata; Arachnida; Araneae;
OC Mygalomorphae; Theraphosidae; Pamphobeteus.
OX NCBI_TaxID=2083160;
RN [1]
RP PROTEIN SEQUENCE, MASS SPECTROMETRY, SUBCELLULAR LOCATION, SYNTHESIS,
RP STRUCTURE BY NMR, FUNCTION, BIOASSAY, AND PHARMACEUTICAL.
RC TISSUE=Venom;
RX PubMed=28106092; DOI=10.1038/srep40883;
RA Deuis J.R., Dekan Z., Wingerd J.S., Smith J.J., Munasinghe N.R.,
RA Bhola R.F., Imlach W.L., Herzig V., Armstrong D.A., Rosengren K.J.,
RA Bosmans F., Waxman S.G., Dib-Hajj S.D., Escoubas P., Minett M.S.,
RA Christie M.J., King G.F., Alewood P.F., Lewis R.J., Wood J.N., Vetter I.;
RT "Pharmacological characterisation of the highly NaV1.7 selective spider
RT venom peptide Pn3a.";
RL Sci. Rep. 7:40883-40883(2017).
RN [2]
RP ERRATUM OF PUBMED:28106092.
RX PubMed=28548111; DOI=10.1038/srep46816;
RA Deuis J.R., Dekan Z., Wingerd J.S., Smith J.J., Munasinghe N.R.,
RA Bhola R.F., Imlach W.L., Herzig V., Armstrong D.A., Rosengren K.J.,
RA Bosmans F., Waxman S.G., Dib-Hajj S.D., Escoubas P., Minett M.S.,
RA Christie M.J., King G.F., Alewood P.F., Lewis R.J., Wood J.N., Vetter I.;
RT "Corrigendum: Pharmacological characterisation of the highly NaV1.7
RT selective spider venom peptide Pn3a.";
RL Sci. Rep. 7:46816-46816(2017).
RN [3]
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).
CC -!- FUNCTION: Gating-modifier toxin that targets voltage-gated sodium
CC channels. According to Deuis et al., 2017, it shows a preferential
CC activity on Nav1.7/SCN9A (Nav1.7/SCN9A (IC(50)=0.9-4.4 nM))
CC (PubMed:28106092). However, another study shows a much less potent
CC activity on Nav1.7/SCN9A (IC(50)=1457 nM) (PubMed:31234412). Also shows
CC weaker effects on hNav1.1/SCN1A (IC(50)=37 nM), hNav1.2/SCN2A
CC (IC(50)=124 nM), hNav1.3/SCN3A (IC(50)=210 nM), hNav1.4/SCN4A
CC (IC(50)=144 nM), hNav1.5/SCN5A (IC(50)=800 nM), hNav1.6/SCN8A
CC (IC(50)=129 nM), hNav1.9/SCN11A (IC(50)=2427 nM) (PubMed:28106092). On
CC Nav1.7/SCN9A, the toxin acts by shifting the voltage-dependence of
CC activation to more depolarized potentials, whereas it does not cause
CC significant effect on the voltage-dependence of activation on other
CC sodium channels (PubMed:28106092). Minor effects are observed on the
CC voltage-dependence of steady-state fast inactivation for all sodium
CC channels tested (Nav1.1/SCN1A-Nav1.8/SCN10A) (PubMed:28106092). By
CC testing the toxin on channel chimera, it has been shown to interact
CC with the S3-S4 linkers in DII and DIV domains of Nav1.7/SCN9A
CC (PubMed:28106092). In vivo, when tested on the OD1-induced mouse model
CC of Nav1.7/SCN9A-mediated pain, the toxin dose-dependently reduces pain
CC behaviors (PubMed:28106092). {ECO:0000269|PubMed:28106092,
CC ECO:0000269|PubMed:31234412}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:28106092}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland.
CC {ECO:0000305|PubMed:28106092}.
CC -!- DOMAIN: The presence of a 'disulfide through disulfide knot'
CC structurally defines this protein as a knottin.
CC {ECO:0000269|PubMed:28106092}.
CC -!- MASS SPECTROMETRY: Mass=4268.5; Method=MALDI; Note=Monoisotopic mass.;
CC Evidence={ECO:0000269|PubMed:28106092};
CC -!- PHARMACEUTICAL: This toxin may represent a lead for the development of
CC novel analgesic agents. When injected with an opioid analgesic drug, it
CC provides an enhanced and effective therapeutic approach to the
CC treatment and/or prevention of pain. {ECO:0000269|PubMed:28106092}.
CC -!- MISCELLANEOUS: Shows no or weak effect on hNav1.8/SCN10A (IC(50)=50
CC uM), rKv2.1/KCNB1 (up to 300 nM) and hCav1.2/CACNA1C, hCav2.2/CACNA1B,
CC alpha-7/SCN9A nAChR, alpha-3/SCN3A nAChR (up to 10 uM).
CC {ECO:0000269|PubMed:28106092}.
CC -!- SIMILARITY: Belongs to the neurotoxin 10 (Hwtx-1) family. 28 (Jztx-11)
CC subfamily. {ECO:0000305}.
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DR PDB; 5T4R; NMR; -; A=1-35.
DR PDBsum; 5T4R; -.
DR AlphaFoldDB; P0DM12; -.
DR SMR; P0DM12; -.
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; IEA:UniProtKB-KW.
DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
DR InterPro; IPR011696; Huwentoxin-1.
DR Pfam; PF07740; Toxin_12; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Direct protein sequencing; Disulfide bond;
KW Ion channel impairing toxin; Knottin; Pharmaceutical; Secreted; Toxin;
KW Voltage-gated sodium channel impairing toxin.
FT CHAIN 1..35
FT /note="Mu-theraphotoxin-Pn3a"
FT /evidence="ECO:0000269|PubMed:28106092"
FT /id="PRO_0000444151"
FT DISULFID 2..16
FT /evidence="ECO:0000269|PubMed:28106092,
FT ECO:0007744|PDB:5T4R"
FT DISULFID 9..21
FT /evidence="ECO:0000269|PubMed:28106092,
FT ECO:0007744|PDB:5T4R"
FT DISULFID 15..28
FT /evidence="ECO:0000269|PubMed:28106092,
FT ECO:0007744|PDB:5T4R"
SQ SEQUENCE 35 AA; 4278 MW; 134EA9BE9DD3C373 CRC64;
DCRYMFGDCE KDEDCCKHLG CKRKMKYCAW DFTFT
