TXP1_PHLXX
ID TXP1_PHLXX Reviewed; 34 AA.
AC P0DM14;
DT 23-MAY-2018, integrated into UniProtKB/Swiss-Prot.
DT 23-MAY-2018, sequence version 1.
DT 25-MAY-2022, entry version 12.
DE RecName: Full=Mu-theraphotoxin-Pspp1 {ECO:0000303|PubMed:31234412, ECO:0000303|PubMed:31443554};
DE Short=Mu-TRTX-Pspp1 {ECO:0000303|PubMed:31234412, ECO:0000303|PubMed:31443554};
DE AltName: Full=Phlotoxin 1 {ECO:0000303|Ref.1};
DE Short=PhlTx1 {ECO:0000303|Ref.1};
OS Phlogiellus sp. (Tarantula).
OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Chelicerata; Arachnida; Araneae;
OC Mygalomorphae; Theraphosidae; Phlogiellus; unclassified Phlogiellus.
OX NCBI_TaxID=2211175;
RN [1]
RP PROTEIN SEQUENCE, FUNCTION, SUBCELLULAR LOCATION, AND SYNTHESIS.
RA Escoubas P., Bosmans F., Cuypers E., Diochot S., Mebs D., Craik D.,
RA Hill J., Maertens C., Nakajima T., Lazdunski M., Tytgat J.;
RT "Phlotoxin-1, a toxin from tarantula venom, is a potent modulator of Nav1.7
RT sodium channels and a potential analgesic.";
RL (In) 15th World Congress on Animal, Plant and Microbial Toxins, pp.220-220,
RL Glasgow, Scotland (2006).
RN [2]
RP PHARMACEUTICAL.
RA Wood J.N.;
RT "Synergistic combination of analgesic drugs.";
RL Patent number EP3046569, 27-JUL-2016.
RN [3]
RP HARMACEUTICAL.
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 [4]
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 [5]
RP FUNCTION, SYNTHESIS, AND AMIDATION AT PHE-34.
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 [6]
RP FUNCTION, SYNTHESIS, MUTAGENESIS OF ALA-1; ASP-7; SER-8; LYS-12; LYS-15;
RP TRP-24; LYS-25 AND TYR-26, 3D-STRUCTURE MODELING, AND AMIDATION AT PHE-34.
RX PubMed=31443554; DOI=10.3390/toxins11090484;
RA Goncalves T.C., Lesport P., Kuylle S., Stura E., Ciolek J., Mourier G.,
RA Servent D., Bourinet E., Benoit E., Gilles N.;
RT "Evaluation of the spider (Phlogiellus genus) Phlotoxin 1 and synthetic
RT variants as antinociceptive drug candidates.";
RL Toxins 11:0-0(2019).
CC -!- FUNCTION: Voltage-gated sodium channel inhibitor. It is unclear if it
CC selectively inhibits Nav1.7/SCN9A or shows similar potency on all
CC sodium channels tested (Ref.1, PubMed:31234412, PubMed:31443554).
CC According to Escoubas et al., 2006 and Nicolas et al., 2019, it is
CC selective over Nav1.7/SCN9A (90% inhibition at 1 uM), versus Nav1.4 and
CC Nav1.6 (35% inhibition), and shows a small inhibition on all other
CC sodium channels (except Nav1.8/SCN10A) (Ref.1, PubMed:31234412).
CC According to Goncalves et al., 2019, it shows a similar inhibition on
CC almost all sodium channels tested (Nav1.1/SCN1A (IC(50)=280.3 nM),
CC Nav1.2/SCN2A (IC(50)=73.7 nM), Nav1.3/SCN3A (IC(50)=201.5 nM),
CC Nav1.4/SCN4A (IC(50)>2100 nM), Nav1.5/SCN5A (IC(50)=710.6 nM),
CC Nav1.6/SCN8A (IC(50)=491.2 nM), and Nav1.7/SCN9A (IC(50)=254.3-260
CC nM)), except Nav1.8/SCN10A (PubMed:31443554). The voltage-dependence of
CC steady-state Nav1.7/SCN9A channel activation and inactivation are not
CC affected, suggesting that is does not act as a gating-modifier toxin
CC but rather blocks or impedes ion flux through the channel pore (Ref.1,
CC PubMed:31234412). The toxin effect is partial and poorly reversible
CC (PubMed:31234412). In addition to its inhibition to sodium channels, it
CC also shows a small inhibition on rat Kv3.4/KCNC4 potassium channels
CC (20% inhibition at 1 uM) (PubMed:31234412). In vivo, when tested on
CC pain models, it shows analgesic activity (PubMed:31234412,
CC PubMed:31443554). {ECO:0000269|PubMed:31234412,
CC ECO:0000269|PubMed:31443554, ECO:0000269|Ref.1}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|Ref.1}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland. {ECO:0000305|Ref.1}.
CC -!- DOMAIN: The presence of a 'disulfide through disulfide knot'
CC structurally defines this protein as a knottin.
CC {ECO:0000250|UniProtKB:P84507}.
CC -!- PHARMACEUTICAL: This toxin may represent a lead for the development of
CC novel analgesic agents. When injected into mice with an opioid
CC analgesic drug and/or an enkephalinase inhibitor, it provides an
CC enhanced and effective therapeutic approach to the treatment and/or
CC prevention of pain (PubMed:28106092, Ref.2). When tested on the OD1-
CC induced mouse model of Nav1.7/SCN9A-mediated pain, it almost completely
CC reverses the induced pain (PubMed:31443554). In addition, it reduces
CC the response of mice in both the acute pain and inflammation phases
CC induced upon formalin injection into the paw (PubMed:31234412).
CC {ECO:0000269|PubMed:28106092, ECO:0000269|PubMed:31234412,
CC ECO:0000269|PubMed:31443554, ECO:0000269|Ref.2}.
CC -!- MISCELLANEOUS: Synthesis and folding of this linear peptide generates 4
CC peaks. Only the peak 1 shows a strong activity against Nav1.7/SCN9A.
CC When analyzed in details, this peak shows two forms (P1' and P1''),
CC which may be explained by the involvement of at least one Pro residue
CC in a cis-trans isomerization. {ECO:0000305|PubMed:31234412,
CC ECO:0000305|PubMed:31443554}.
CC -!- MISCELLANEOUS: Does not show inhibition on mKv1.1/KCNA1, rKv1.2/KCNA2,
CC rKv1.3/KCNA3, rKv1.4/KCNA4, mKv1.5/KCNA5, rKv1.6/KCNA6, rKv2.1,
CC rKv2.2/KCNB2, rKv3.1/KCNC1, rKv3.2/KCNC2, mKv4.1/KCND1, rKv4.2/KCND2,
CC dog Kv4.3/KCND3, KT3.1/KCNK3, rKir1.1/KCNJ1, mKir2.3/KCNJ4
CC (PubMed:31234412). Shows no or weak activity on Cav1.2/CACNA1C
CC (IC(50)=5.9 uM), Kv11.1/KCNH2/ERG1/HERG (IC(50)>10 uM), and
CC Nav1.8/SCN10A (IC(50)>10 uM) (PubMed:31443554).
CC {ECO:0000269|PubMed:31234412, ECO:0000269|PubMed:31443554}.
CC -!- SIMILARITY: Belongs to the neurotoxin 10 (Hwtx-1) family.
CC {ECO:0000305}.
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DR AlphaFoldDB; P0DM14; -.
DR SMR; P0DM14; -.
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 Amidation; Direct protein sequencing; Disulfide bond;
KW Ion channel impairing toxin; Knottin; Pharmaceutical; Secreted; Toxin;
KW Voltage-gated sodium channel impairing toxin.
FT CHAIN 1..34
FT /note="Mu-theraphotoxin-Pspp1"
FT /evidence="ECO:0000269|Ref.1"
FT /id="PRO_0000444153"
FT MOD_RES 34
FT /note="Phenylalanine amide"
FT /evidence="ECO:0000305|PubMed:31234412,
FT ECO:0000305|PubMed:31443554"
FT DISULFID 2..17
FT /evidence="ECO:0000250|UniProtKB:P84507"
FT DISULFID 9..22
FT /evidence="ECO:0000250|UniProtKB:P84507"
FT DISULFID 16..29
FT /evidence="ECO:0000250|UniProtKB:P84507"
FT MUTAGEN 1
FT /note="A->Q: When modified in pyroglutamic acid; weak
FT change in ability to inhibit Nav1.7/SCN9A."
FT /evidence="ECO:0000269|PubMed:31443554"
FT MUTAGEN 7
FT /note="D->A: Moderate increase (about 5-fold) in ability to
FT inhibit Nav1.2/SCN2A, Nav1.5/SCN5A, and Nav1.7/SCN9A, gain
FT of ability to inhibit Nav1.8/SCN10A and important increase
FT in ability to inhibit Cav1.2/CACNA1C (7300-fold). Similar
FT analgesic activity, when tested on the OD1-induced mouse
FT model of Nav1.7/SCN9A-mediated pain."
FT /evidence="ECO:0000269|PubMed:31443554"
FT MUTAGEN 8
FT /note="S->A: Weak change in ability to inhibit
FT Nav1.7/SCN9A."
FT /evidence="ECO:0000269|PubMed:31443554"
FT MUTAGEN 12
FT /note="K->A: Weak change in ability to inhibit
FT Nav1.7/SCN9A."
FT /evidence="ECO:0000269|PubMed:31443554"
FT MUTAGEN 15
FT /note="K->A: Weak change in ability to inhibit
FT Nav1.7/SCN9A."
FT /evidence="ECO:0000269|PubMed:31443554"
FT MUTAGEN 24
FT /note="W->A: 40-fold decrease in ability to inhibit
FT Nav1.7/SCN9A."
FT /evidence="ECO:0000269|PubMed:31443554"
FT MUTAGEN 25
FT /note="K->A: 40-fold decrease in ability to inhibit
FT Nav1.7/SCN9A."
FT /evidence="ECO:0000269|PubMed:31443554"
FT MUTAGEN 26
FT /note="Y->A: 40-fold decrease in ability to inhibit
FT Nav1.7/SCN9A."
FT /evidence="ECO:0000269|PubMed:31443554"
SQ SEQUENCE 34 AA; 4065 MW; 2D5DCA8E5195744A CRC64;
ACLGQWDSCD PKASKCCPNY ACEWKYPWCR YKLF
