TXPR1_BUMPU
ID TXPR1_BUMPU Reviewed; 35 AA.
AC P0DQN3;
DT 02-DEC-2020, integrated into UniProtKB/Swiss-Prot.
DT 02-DEC-2020, sequence version 1.
DT 25-MAY-2022, entry version 6.
DE RecName: Full=Beta/omega-theraphotoxin-Bp1a {ECO:0000303|PubMed:32511987};
DE Short=Beta/omega-TRTX-Bp1a {ECO:0000303|PubMed:32511987};
DE AltName: Full=Protoxin-I analog {ECO:0000305};
DE Short=ProTx-I analog {ECO:0000305};
OS Bumba pulcherrimaklaasi (Tarantula spider) (Euathlus pulcherrimaklaasi).
OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Chelicerata; Arachnida; Araneae;
OC Mygalomorphae; Theraphosidae; Bumba.
OX NCBI_TaxID=2024411;
RN [1]
RP PROTEIN SEQUENCE, FUNCTION, SUBCELLULAR LOCATION, RECOMBINANT EXPRESSION,
RP AND MUTAGENESIS OF LEU-6; LYS-17; LEU-19; TRP-27; VAL-29; TRP-30 AND
RP ASP-31.
RC TISSUE=Venom;
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).
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) as well as the nociceptor cation channel TRPA1
CC (IC(50)=389 nM) (By similarity) (PubMed:32511987). Acts as a potent and
CC selective blocker of voltage-gated calcium channel Cav3.1/CACNA1G, but
CC not of Cav3.2/CACNA1H, and Cav3.3/CACNA1I (By similarity). On
CC Nav1.7/SCN9A, primarily interacts with the DII and DIV voltage-sensor
CC domains (PubMed:32511987). Also acts as an inhibitor of nociceptor
CC cation channel TRPA1 (IC(50)~389 nM) by binding to the S1-S4 gating
CC domain of TRPA1 (By similarity). It shows moderate affinity for lipid
CC bilayers (By similarity). {ECO:0000250|UniProtKB:P83480,
CC ECO:0000269|PubMed:32511987}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:32511987}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland.
CC {ECO:0000305|PubMed:32511987}.
CC -!- DOMAIN: The presence of a 'disulfide through disulfide knot'
CC structurally defines this protein as a knottin.
CC {ECO:0000250|UniProtKB:P83480}.
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 Nav1.7/SCN9A.
CC {ECO:0000269|PubMed:32511987}.
CC -!- PHARMACEUTICAL: The amidated mutant G32A (ProTx-I-G32A-NH2) shows a
CC decreased toxin ability to inhibit all sodium channels tested, with a
CC more 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 ProTx-1 from Thrixopelma pruriens (AC P83480).
CC {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the neurotoxin 10 (Hwtx-1) family. 54 (ProTx-1)
CC subfamily. {ECO:0000305}.
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DR AlphaFoldDB; P0DQN3; -.
DR SMR; P0DQN3; -.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0005246; F:calcium channel regulator activity; IEA:UniProtKB-KW.
DR GO; GO:0008200; F:ion channel inhibitor activity; IEA:InterPro.
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; IEA:UniProtKB-KW.
DR InterPro; IPR011696; Huwentoxin-1.
DR Pfam; PF07740; Toxin_12; 1.
PE 1: Evidence at protein level;
KW Calcium channel impairing toxin; Direct protein sequencing; Disulfide bond;
KW Ion channel impairing toxin; Knottin; Neurotoxin; Pharmaceutical;
KW 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-Bp1a"
FT /evidence="ECO:0000269|PubMed:32511987"
FT /id="PRO_0000451453"
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:0000250|UniProtKB:P83480"
FT DISULFID 9..21
FT /evidence="ECO:0000250|UniProtKB:P83480"
FT DISULFID 15..28
FT /evidence="ECO:0000250|UniProtKB:P83480"
FT MUTAGEN 6
FT /note="L->A: Decrease in ability to inhibit Nav1.7/SCN9A."
FT /evidence="ECO:0000269|PubMed:32511987"
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 Nav1.7/SCN9A."
FT /evidence="ECO:0000269|PubMed:32511987"
FT MUTAGEN 27
FT /note="W->A: Decrease in ability to inhibit Nav1.7/SCN9A."
FT /evidence="ECO:0000269|PubMed:32511987"
FT MUTAGEN 29
FT /note="V->A: Decrease in ability to inhibit Nav1.7/SCN9A."
FT /evidence="ECO:0000269|PubMed:32511987"
FT MUTAGEN 30
FT /note="W->A: Decrease in ability to inhibit Nav1.7/SCN9A."
FT /evidence="ECO:0000269|PubMed:32511987"
FT MUTAGEN 31
FT /note="D->A: Decrease in ability to inhibit Nav1.7/SCN9A."
FT /evidence="ECO:0000269|PubMed:32511987"
SQ SEQUENCE 35 AA; 3994 MW; 13F35B2F3A59B2A5 CRC64;
ECRYWLGGCS AGQTCCKHLV CSRRHGWCVW DGTFS
