CA1D_CONTE
ID CA1D_CONTE Reviewed; 37 AA.
AC K8DWB5;
DT 12-APR-2017, integrated into UniProtKB/Swiss-Prot.
DT 06-FEB-2013, sequence version 1.
DT 25-MAY-2022, entry version 29.
DE RecName: Full=Alpha-conotoxin TxID {ECO:0000303|PubMed:24200193};
DE AltName: Full=Alpha-conotoxin TxIC {ECO:0000312|EMBL:CCN27219.1};
DE Flags: Precursor; Fragment;
OS Conus textile (Cloth-of-gold cone).
OC Eukaryota; Metazoa; Spiralia; Lophotrochozoa; Mollusca; Gastropoda;
OC Caenogastropoda; Neogastropoda; Conoidea; Conidae; Conus; Cylinder.
OX NCBI_TaxID=6494;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], SYNTHESIS OF 22-36, AMIDATION AT CYS-36,
RP STRUCTURE BY NMR OF 22-36, AND DISULFIDE BONDS.
RX PubMed=24200193; DOI=10.1021/jm401254c;
RA Luo S., Zhangsun D., Zhu X., Wu Y., Hu Y., Christensen S., Harvey P.J.,
RA Akcan M., Craik D.J., McIntosh J.M.;
RT "Characterization of a novel alpha-conotoxin TxID from Conus textile that
RT potently blocks rat alpha3beta4 nicotinic acetylcholine receptors.";
RL J. Med. Chem. 56:9655-9663(2013).
RN [2]
RP MUTAGENESIS OF GLY-22; SER-25; HIS-26; PRO-27; VAL-28; SER-30; MET-32;
RP SER-33; PRO-34 AND ILE-35.
RX PubMed=28603989; DOI=10.1021/acs.jmedchem.7b00546;
RA Wu Y., Zhangsun D., Zhu X., Kaas Q., Zhangsun M., Harvey P.J., Craik D.J.,
RA McIntosh J.M., Luo S.;
RT "Alpha-conotoxin [S9A]TxID potently discriminates between alpha3beta4 and
RT alpha6/alpha3beta4 nicotinic acetylcholine receptors.";
RL J. Med. Chem. 60:5826-5833(2017).
RN [3]
RP MUTAGENESIS OF SER-30, AND 3D-STRUCTURE MODELING OF TXID IN COMPLEX WITH
RP ALPHA-3-BETA-4 OR ALPHA-6-BETA-4.
RX PubMed=30252466; DOI=10.1021/acs.jmedchem.8b00967;
RA Yu J., Zhu X., Harvey P.J., Kaas Q., Zhangsun D., Craik D.J., Luo S.;
RT "A single amino acid substitution in alpha-conotoxin TxID reveals a
RT specific alpha3beta4 nicotinic acetylcholine receptor antagonist.";
RL J. Med. Chem. 61:9256-9265(2018).
RN [4]
RP MUTAGENESIS OF MET-32.
RX PubMed=29925760; DOI=10.3390/md16060215;
RA Ren J., Li R., Ning J., Zhu X., Zhangsun D., Wu Y., Luo S.;
RT "Effect of methionine oxidation and substitution of alpha-conotoxin TxID on
RT alpha3beta4 nicotinic acetylcholine receptor.";
RL Mar. Drugs 16:0-0(2018).
CC -!- FUNCTION: Alpha-conotoxins act on postsynaptic membranes, they bind to
CC the nicotinic acetylcholine receptors (nAChR) and thus inhibit them.
CC This toxin inhibits alpha-3-beta-4/CHRNA3-CHRNB4 (IC(50)=3.6-18.38 nM),
CC alpha-6/alpha-3-beta-4 (CHRNA6/CHRNA3-CHRNB2-CHRNB4) (IC(50)=33.9-94.1
CC nM), and alpha-2-beta-4/CHRNA2-CHRNB4 (IC(50)=4550 nM) nAChRs
CC (PubMed:24200193, PubMed:28603989, PubMed:29925760). The toxin competes
CC with agonists in the orthosteric binding site of alpha-3-beta-4/CHRNA3-
CC CHRNB4 and alpha-6-beta-4/CHRNA6-CHRNB4 (PubMed:30252466).
CC {ECO:0000269|PubMed:24200193, ECO:0000269|PubMed:28603989,
CC ECO:0000269|PubMed:29925760, ECO:0000305|PubMed:30252466}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000305|PubMed:24200193}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom duct.
CC {ECO:0000305|PubMed:24200193}.
CC -!- DOMAIN: The cysteine framework is I (CC-C-C). Alpha4/6 pattern.
CC {ECO:0000305}.
CC -!- PTM: Unmodified Met-32 is essential for toxin binding to rat alpha-3-
CC beta-4/CHRNA3-CHRNB4 nAChR. An oxidation of this methionine provokes a
CC 13.3-fold decrease in inhibitory potency (IC(50)=245 nM instead of 18
CC nM). Owing to its potent activity, derivatives of this toxin have a
CC potential in the development of a novel drug. Unfortunately, the
CC oxidation of the methionine is readily to happen during toxin synthesis
CC and oxidation steps as well as under oxidative environment in vivo,
CC which should still be considered to find a solution to this major
CC drawback. {ECO:0000269|PubMed:29925760}.
CC -!- MISCELLANEOUS: This toxin does not show inhibition at neuronal alpha-4-
CC beta-4/CHRNA4-CHRNB4, alpha-4-beta-2/CHRNA4-CHRNB2, alpha-6/alpha-3-
CC beta-2-beta-3 (CHRNA6/CHRNA3-CHRNB2-CHRNB3), alpha-3-beta-2/CHRNA3-
CC CHRNB2, alpha-2-beta-2/CHRNA2-CHRNB2, alpha-9-alpha-10/CHRNA9-CHRNA10,
CC alpha-7/CHRNA7 nAChRs and muscle alpha-1-beta-1-delta-epsilon/CHRNA1-
CC CHRNB1-CHRND-CHRNE nAChR (PubMed:24200193).
CC {ECO:0000269|PubMed:24200193}.
CC -!- SIMILARITY: Belongs to the conotoxin A superfamily. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Biological Magnetic Resonance Data Bank;
CC URL="http://www.bmrb.wisc.edu/data_library/summary/index.php?bmrbId=18964";
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DR EMBL; HF543950; CCN27219.1; -; Genomic_DNA.
DR PDB; 2M3I; NMR; -; A=16-30.
DR PDBsum; 2M3I; -.
DR AlphaFoldDB; K8DWB5; -.
DR MetOSite; K8DWB5; -.
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:0090729; F:toxin activity; IEA:UniProtKB-KW.
DR InterPro; IPR009958; Conotoxin_a-typ.
DR Pfam; PF07365; Toxin_8; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylcholine receptor inhibiting toxin; Amidation;
KW Disulfide bond; Neurotoxin; Postsynaptic neurotoxin; Secreted; Toxin.
FT PROPEP <1..21
FT /evidence="ECO:0000305"
FT /id="PRO_0000439430"
FT PEPTIDE 22..36
FT /note="Alpha-conotoxin TxID"
FT /evidence="ECO:0000305|PubMed:24200193"
FT /id="PRO_0000439431"
FT MOD_RES 36
FT /note="Cysteine amide"
FT /evidence="ECO:0000305|PubMed:24200193"
FT DISULFID 23..29
FT /evidence="ECO:0000305|PubMed:24200193,
FT ECO:0000312|PDB:2M3I"
FT DISULFID 24..36
FT /evidence="ECO:0000305|PubMed:24200193,
FT ECO:0000312|PDB:2M3I"
FT MUTAGEN 22
FT /note="G->A: 17-fold and 8-fold decrease in inhibitory
FT potency on alpha-3-beta-4/CHRNA3-CHRNB4 and alpha-6-beta-
FT 4/CHRNA6-CHRNB4 nAChRs, respectively."
FT /evidence="ECO:0000269|PubMed:28603989"
FT MUTAGEN 25
FT /note="S->A: 3-fold and 2-fold decrease in inhibitory
FT potency on alpha-3-beta-4/CHRNA3-CHRNB4 and alpha-6-beta-
FT 4/CHRNA6-CHRNB4 nAChRs, respectively."
FT /evidence="ECO:0000269|PubMed:28603989"
FT MUTAGEN 26
FT /note="H->A: Complete loss in inhibitory potency on both
FT alpha-3-beta-4/CHRNA3-CHRNB4 and alpha-6-beta-4/CHRNA6-
FT CHRNB4 nAChRs."
FT /evidence="ECO:0000269|PubMed:28603989"
FT MUTAGEN 27
FT /note="P->A: Complete loss in inhibitory potency on both
FT alpha-3-beta-4/CHRNA3-CHRNB4 and alpha-6-beta-4/CHRNA6-
FT CHRNB4 nAChRs."
FT /evidence="ECO:0000269|PubMed:28603989"
FT MUTAGEN 28
FT /note="V->A: Complete loss in inhibitory potency on both
FT alpha-3-beta-4/CHRNA3-CHRNB4 and alpha-6-beta-4/CHRNA6-
FT CHRNB4 nAChRs."
FT /evidence="ECO:0000269|PubMed:28603989"
FT MUTAGEN 30
FT /note="S->A: 46-fold increase in selectivity for alpha-3-
FT beta-4/CHRNA3-CHRNB4 over alpha-6-beta-4/CHRNA6-CHRNB4
FT nAChRs. 1.1-fold and 5.2-fold decrease in inhibitory
FT potency on alpha-3-beta-4/CHRNA3-CHRNB4 and alpha-6-beta-
FT 4/CHRNA6-CHRNB4 nAChRs, respectively."
FT /evidence="ECO:0000269|PubMed:28603989"
FT MUTAGEN 30
FT /note="S->K: Become completely selective for alpha-3-beta-
FT 4/CHRNA3-CHRNB4 over alpha-6-beta-4/CHRNA6-CHRNB4 nAChRs.
FT 2-fold decrease in inhibitory potency on alpha-3-beta-
FT 4/CHRNA3-CHRNB4 and loss of activity on alpha-6-beta-
FT 4/CHRNA6-CHRNB4 nAChRs, respectively."
FT /evidence="ECO:0000269|PubMed:30252466"
FT MUTAGEN 32
FT /note="M->A: Complete loss in inhibitory potency on both
FT alpha-3-beta-4/CHRNA3-CHRNB4 and alpha-6-beta-4/CHRNA6-
FT CHRNB4 nAChRs."
FT /evidence="ECO:0000269|PubMed:28603989"
FT MUTAGEN 32
FT /note="M->E,K,Q,R: Complete loss in inhibitory potency on
FT both alpha-3-beta-4/CHRNA3-CHRNB4 nAChRs."
FT /evidence="ECO:0000269|PubMed:29925760"
FT MUTAGEN 32
FT /note="M->I: 21-fold and 1.5-fold decrease in inhibitory
FT potency on alpha-3-beta-4/CHRNA3-CHRNB4 and alpha-6-beta-
FT 4/CHRNA6-CHRNB4 nAChRs, respectively."
FT /evidence="ECO:0000269|PubMed:28603989"
FT MUTAGEN 32
FT /note="M->L,V: Important decrease in inhibitory potency on
FT alpha-3-beta-4/CHRNA3-CHRNB4."
FT /evidence="ECO:0000269|PubMed:29925760"
FT MUTAGEN 33
FT /note="S->A: 5-fold and 1.2-fold decrease in inhibitory
FT potency on alpha-3-beta-4/CHRNA3-CHRNB4 and alpha-6-beta-
FT 4/CHRNA6-CHRNB4 nAChRs, respectively."
FT /evidence="ECO:0000269|PubMed:28603989"
FT MUTAGEN 34
FT /note="P->A: Complete loss in inhibitory potency on both
FT alpha-3-beta-4/CHRNA3-CHRNB4 and alpha-6-beta-4/CHRNA6-
FT CHRNB4 nAChRs."
FT /evidence="ECO:0000269|PubMed:28603989"
FT MUTAGEN 35
FT /note="I->A: 4.4-fold and 1.3-fold decrease in inhibitory
FT potency on alpha-3-beta-4/CHRNA3-CHRNB4 and alpha-6-beta-
FT 4/CHRNA6-CHRNB4 nAChRs, respectively."
FT /evidence="ECO:0000269|PubMed:28603989"
FT NON_TER 1
SQ SEQUENCE 37 AA; 3774 MW; 066ED035FF4B52F6 CRC64;
FDGRNAAGND KMSALMALTT RGCCSHPVCS AMSPICG
