CO1EA_CONGR
ID CO1EA_CONGR Reviewed; 74 AA.
AC J7GY56; A0A0E3SZW7;
DT 01-OCT-2014, integrated into UniProtKB/Swiss-Prot.
DT 23-MAY-2018, sequence version 2.
DT 25-MAY-2022, entry version 24.
DE RecName: Full=Alpha-conotoxin GeXIVA {ECO:0000305};
DE AltName: Full=Alpha-O-conotoxin GeXIVA {ECO:0000303|PubMed:26170295};
DE AltName: Full=Conotoxin Ge14.1 {ECO:0000312|EMBL:AFP87476.1};
DE AltName: Full=Conotoxin GeXIVAWT {ECO:0000303|PubMed:22825834};
DE Flags: Precursor;
OS Conus generalis (General cone).
OC Eukaryota; Metazoa; Spiralia; Lophotrochozoa; Mollusca; Gastropoda;
OC Caenogastropoda; Neogastropoda; Conoidea; Conidae; Conus; Strategoconus.
OX NCBI_TaxID=101304;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], SYNTHESIS OF 47-74, AND FUNCTION.
RC TISSUE=Venom duct;
RX PubMed=22825834; DOI=10.1007/s00253-012-4287-6;
RA Gao B., Zhangsun D., Wu Y., Lin B., Zhu X., Luo S.;
RT "Expression, renaturation and biological activity of recombinant conotoxin
RT GeXIVAWT.";
RL Appl. Microbiol. Biotechnol. 97:1223-1230(2013).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], SYNTHESIS OF 47-74 (BEAD, RIBBON AND GLOBULAR
RP ISOMERS), FUNCTION, 3D-STRUCTURE MODELING (RIBBON ISOMER (I-IV; II-III)),
RP MUTAGENESIS OF ASP-71, AND PHARMACEUTICAL.
RC TISSUE=Venom duct;
RX PubMed=26170295; DOI=10.1073/pnas.1503617112;
RA Luo S., Zhangsun D., Harvey P.J., Kaas Q., Wu Y., Zhu X., Hu Y., Li X.,
RA Tsetlin V.I., Christensen S., Romero H.K., McIntyre M., Dowell C.,
RA Baxter J.C., Elmslie K.S., Craik D.J., McIntosh J.M.;
RT "Cloning, synthesis, and characterization of alpha-O-conotoxin GeXIVA, a
RT potent alpha9alpha10 nicotinic acetylcholine receptor antagonist.";
RL Proc. Natl. Acad. Sci. U.S.A. 112:E4026-E4035(2015).
RN [3]
RP BIOASSAY IN RAT PAIN MODEL, AND PHARMACEUTICAL.
RX PubMed=26706456; DOI=10.1016/j.pnpbp.2015.12.005;
RA Li X., Hu Y., Wu Y., Huang Y., Yu S., Ding Q., Zhangsun D., Luo S.;
RT "Anti-hypersensitive effect of intramuscular administration of alphaO-
RT conotoxin GeXIVA[1,2] and GeXIVA[1,4] in rats of neuropathic pain.";
RL Prog. Neuro-Psychopharmacol. Biol. Psychiatry 66:112-119(2016).
RN [4]
RP FUNCTION, MUTAGENESIS OF CYS-48; CYS-55; CYS-66 AND CYS-73, AND
RP 3D-STRUCTURE MODELING.
RX PubMed=31986036; DOI=10.1021/acs.jmedchem.9b01409;
RA Xu P., Kaas Q., Wu Y., Zhu X., Li X., Harvey P.J., Zhangsun D., Craik D.J.,
RA Luo S.;
RT "Structure and activity studies of disulfide-deficient analogues of alphaO-
RT Conotoxin GeXIVA.";
RL J. Med. Chem. 63:1564-1575(2020).
CC -!- FUNCTION: Alpha-conotoxins act on postsynaptic membranes, they bind to
CC the nicotinic acetylcholine receptors (nAChR) and thus inhibit them.
CC This toxin is very potent on alpha-9-alpha-10/CHRNA9-CHRNA10 nAChR
CC (IC(50)=4.61-12 nM for the bead isomer (I-II; III-IV), IC(50)=7-16 nM
CC for the ribbon isomer (I-IV; II-III) and IC(50)=22.7 nM for the
CC globular isomer (I-III; II-IV)) (PubMed:26170295, PubMed:31986036). The
CC bead isomer also shows a weak inhibition on other nAChRs (alpha-1-beta-
CC 1-delta-epsilon/CHRNA1-CHRNB1-CHRND-CHRNE, alpha-7/CHRNA7, alpha-
CC 6/alpha-3-beta-2-beta-3 (CHRNA6/CHRNA3-CHRNB2-CHRNB3), alpha-3-beta-
CC 2/CHRNA3-CHRNB2, alpha-2-beta-2/CHRNA2-CHRNB2, alpha-6/alpha-3-beta-4
CC (CHRNA6/CHRNA3-CHRNB4), alpha-4-beta-2/CHRNA4-CHRNB2, alpha-4-beta-
CC 4/CHRNA4-CHRNB4, alpha-2-beta-4/CHRNA2-CHRNB4, alpha-3-beta-4/CHRNA3-
CC CHRNB4) (PubMed:26170295, PubMed:31986036). The toxin blockade is
CC voltage-dependent, and its binding site does not overlap with the
CC binding site of the competitive antagonist alpha-conotoxin RgIA
CC (PubMed:26170295). The toxin inhibits Sf9 cell growth
CC (PubMed:22825834). Both the bead and ribbon isomers relieve pain
CC effects in the rat chronic constriction injury (CCI) model of
CC neuropathic pain, and in the acute pain model of tail flick test, but
CC have no effect on motor performance (PubMed:26170295, PubMed:26706456).
CC {ECO:0000269|PubMed:22825834, ECO:0000269|PubMed:26170295,
CC ECO:0000269|PubMed:26706456, ECO:0000269|PubMed:31986036}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000305|PubMed:22825834}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom duct.
CC {ECO:0000305|PubMed:22825834}.
CC -!- DOMAIN: The cysteine framework is XIV (C-C-C-C). {ECO:0000305}.
CC -!- PTM: The native disulfide bond pairing has not been studied. Three
CC isomers may exist: the bead isomer (I-II; III-IV), the globular isomer
CC (I-III; II-IV), the ribbon isomer (I-IV; II-III). They have all been
CC synthesized and their activity tested (PubMed:26170295). All of them
CC show similar potency on alpha-9-alpha-10 (CHRNA9-CHRNA10) nAChR,
CC showing that disulfide bonds does not significantly affect their
CC activity (PubMed:26170295). In addition, removal of disulfide bonds
CC does not affect the activity on alpha-9-alpha-10 (CHRNA9-CHRNA10) nAChR
CC either (PubMed:31986036). {ECO:0000269|PubMed:26170295,
CC ECO:0000269|PubMed:31986036}.
CC -!- PHARMACEUTICAL: Is a promising analgesic drug candidate. It shows
CC analgesic effect without the development of tolerance and retains its
CC effect two weeks after drug withdrawal. {ECO:0000269|PubMed:26170295,
CC ECO:0000269|PubMed:26706456}.
CC -!- MISCELLANEOUS: This toxin (both bead (I-II; III-IV) and ribbon (I-IV;
CC II-III) isomers) does not inhibit voltage-gated calcium channels from
CC DRG neurons (Cav1.2/CACNA1C, Cav2.1/CACNA1A, Cav2.2/CACNA1B and
CC Cav2.3/CACNA1E). {ECO:0000269|PubMed:26170295}.
CC -!- SIMILARITY: Belongs to the conotoxin O1 superfamily. {ECO:0000305}.
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DR EMBL; JX198170; AFP87476.1; -; mRNA.
DR EMBL; KP793740; AKB95553.1; -; mRNA.
DR AlphaFoldDB; J7GY56; -.
DR SMR; J7GY56; -.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0035792; C:host cell postsynaptic membrane; IEA:UniProtKB-KW.
DR GO; GO:0030550; F:acetylcholine receptor inhibitor activity; IEA:UniProtKB-KW.
DR GO; GO:0008200; F:ion channel inhibitor activity; IEA:InterPro.
DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
DR InterPro; IPR004214; Conotoxin.
DR Pfam; PF02950; Conotoxin; 1.
PE 1: Evidence at protein level;
KW Acetylcholine receptor inhibiting toxin; Disulfide bond; Neurotoxin;
KW Pharmaceutical; Postsynaptic neurotoxin; Secreted; Signal; Toxin.
FT SIGNAL 1..22
FT /evidence="ECO:0000255"
FT PROPEP 23..46
FT /evidence="ECO:0000305"
FT /id="PRO_0000430420"
FT PEPTIDE 47..74
FT /note="Alpha-conotoxin GeXIVA"
FT /evidence="ECO:0000305|PubMed:22825834"
FT /id="PRO_0000430421"
FT REGION 56..64
FT /note="Interacts with alpha-9-alpha-10 (CHRNA9-CHRNA10)
FT nAChR"
FT /evidence="ECO:0000269|PubMed:26170295"
FT MUTAGEN 48
FT /note="C->A: In [C2A;C9A;C20S;C27S] GeXIVA; important
FT increase in specificity towards alpha-9-alpha-10/CHRNA9-
FT CHRNA10 nAChR."
FT /evidence="ECO:0000269|PubMed:31986036"
FT MUTAGEN 55
FT /note="C->A: In [C2A;C9A;C20S;C27S] GeXIVA; important
FT increase in specificity towards alpha-9-alpha-10/CHRNA9-
FT CHRNA10 nAChR."
FT /evidence="ECO:0000269|PubMed:31986036"
FT MUTAGEN 66
FT /note="C->S: In [C2A;C9A;C20S;C27S] GeXIVA; important
FT increase in specificity towards alpha-9-alpha-10/CHRNA9-
FT CHRNA10 nAChR."
FT /evidence="ECO:0000269|PubMed:31986036"
FT MUTAGEN 71
FT /note="D->A,N: 4-fold decrease in inhibition of alpha-9-
FT alpha-10 (CHRNA9-CHRNA10) nAChR (ribbon isomer (I-IV; II-
FT III))."
FT /evidence="ECO:0000269|PubMed:26170295"
FT MUTAGEN 73
FT /note="C->S: In [C2A;C9A;C20S;C27S] GeXIVA; important
FT increase in specificity towards alpha-9-alpha-10/CHRNA9-
FT CHRNA10 nAChR."
FT /evidence="ECO:0000269|PubMed:31986036"
FT CONFLICT 61
FT /note="R -> C (in Ref. 1; AFP87476)"
SQ SEQUENCE 74 AA; 8621 MW; D2390E2716A9CE59 CRC64;
MKLTCVLIIT VLFLTACQLT TAVTYSRGEH KHRALMSTGT NYRLPKTCRS SGRYCRSPYD
RRRRYCRRIT DACV
