CA1A_CONOM
ID CA1A_CONOM Reviewed; 17 AA.
AC P0C1R7;
DT 25-JUL-2006, integrated into UniProtKB/Swiss-Prot.
DT 25-JUL-2006, sequence version 1.
DT 03-AUG-2022, entry version 54.
DE RecName: Full=Alpha-conotoxin OmIA {ECO:0000303|PubMed:16678128, ECO:0000303|PubMed:16803900};
DE Flags: Precursor;
OS Conus omaria (Omaria cone).
OC Eukaryota; Metazoa; Spiralia; Lophotrochozoa; Mollusca; Gastropoda;
OC Caenogastropoda; Neogastropoda; Conoidea; Conidae; Conus; Darioconus.
OX NCBI_TaxID=89429;
RN [1]
RP PROTEIN SEQUENCE, FUNCTION, SYNTHESIS, AMIDATION AT GLY-17, DISULFIDE
RP BONDS, MASS SPECTROMETRY, AND SUBCELLULAR LOCATION.
RC TISSUE=Venom;
RX PubMed=16803900; DOI=10.1074/jbc.m602969200;
RA Talley T.T., Olivera B.M., Han K.-H., Christensen S.B., Dowell C.,
RA Tsigelny I., Ho K.-Y., Taylor P., McIntosh J.M.;
RT "Alpha-conotoxin OmIA is a potent ligand for the acetylcholine-binding
RT protein as well as alpha3beta2 and alpha7 nicotinic acetylcholine
RT receptors.";
RL J. Biol. Chem. 281:24678-24686(2006).
RN [2]
RP FUNCTION ON ALPHA-7/CHRNA7 NACHR, AND SYNTHESIS.
RX PubMed=30025921; DOI=10.1016/j.neuropharm.2018.07.019;
RA Yu J., Zhu X., Zhang L., Kudryavtsev D., Kasheverov I., Lei Y.,
RA Zhangsun D., Tsetlin V., Luo S.;
RT "Species specificity of rat and human alpha7 nicotinic acetylcholine
RT receptors towards different classes of peptide and protein antagonists.";
RL Neuropharmacology 139:226-237(2018).
RN [3]
RP X-RAY CRYSTALLOGRAPHY (2.47 ANGSTROMS) IN COMPLEX WITH LYMNAE STAGNALIS
RP ACETYLCHOLINE BINDING PROTEIN, FUNCTION, SYNTHESIS, 3D-STRUCTURE MODELING
RP IN COMPLEX WITH ALPHA-7 NICOTINIC ACETYLCHOLINE RECEPTOR, AND MUTAGENESIS
RP OF HIS-5; ASN-9; VAL-10 AND ASN-11.
RX PubMed=34955864; DOI=10.3389/fphar.2021.803397;
RA Ho T.N.T., Abraham N., Lewis R.J.;
RT "Unique pharmacological properties of alpha-conotoxin OmIA at alpha7
RT nAChRs.";
RL Front. Pharmacol. 12:803397-803397(2021).
RN [4]
RP STRUCTURE BY NMR, SYNTHESIS, AMIDATION AT GLY-17, AND DISULFIDE BONDS.
RX PubMed=16678128; DOI=10.1016/j.bbrc.2006.04.099;
RA Chi S.-W., Kim D.-H., Olivera B.M., McIntosh J.M., Han K.-H.;
RT "Solution conformation of a neuronal nicotinic acetylcholine receptor
RT antagonist alpha-conotoxin OmIA that discriminates alpha3 vs. alpha6 nAChR
RT subtypes.";
RL Biochem. Biophys. Res. Commun. 345:248-254(2006).
CC -!- FUNCTION: Alpha-conotoxins act on postsynaptic membranes, they bind to
CC the nicotinic acetylcholine receptors (nAChR) and thus inhibit them.
CC This toxin blocks alpha-3-beta-2/CHRNA3-CHRNB2 (IC(50)=11 nM), alpha-
CC 7/CHRNA7 (IC(50)=27.1-59 nM (rat)/ 290 nM (human)), alpha-3-beta-
CC 4/CHRNA3-CHRNB4 (IC(50)=160 nM), and alpha-6/alpha-3-beta-2-beta-3
CC (CHRNA6/CHRNA3-CHRNB2-CHRNB3) (IC(50)=201 nM) nAChR (PubMed:16803900,
CC PubMed:30025921, PubMed:34955864). In the OmIA-AChBP complex, this
CC toxin occupies all five binding pockets located between two adjacent
CC subunits of the homopentamer (PubMed:34955864). Despite a competitive
CC binding mode observed in the co-crystal structure, it displays
CC functional insurmountable antagonism at alpha-7 and alpha-3-beta-4
CC nAChRs (PubMed:34955864). It also shows biphasic-inhibition at alpha-7
CC nAChRs in the presence of the positive allosteric modulator PNU120596,
CC with a preference for the high-affinity binding site following
CC prolonged exposure (PubMed:34955864). {ECO:0000269|PubMed:16803900,
CC ECO:0000269|PubMed:30025921, ECO:0000269|PubMed:34955864}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:16803900}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom duct.
CC {ECO:0000305|PubMed:16803900}.
CC -!- DOMAIN: The cysteine framework is I (CC-C-C). Alpha4/7 pattern.
CC {ECO:0000305}.
CC -!- MASS SPECTROMETRY: Mass=1720.7; Method=LSI;
CC Evidence={ECO:0000269|PubMed:16803900};
CC -!- MISCELLANEOUS: This toxin has no effect on alpha-1-beta-1-delta-
CC epsilon/CHRNA1-CHRNB1-CHRND-CHRNE, alpha-2-beta-2/CHRNA2-CHRNB2, and
CC alpha-4-beta-2/CHRNA4-CHRNB2 nAChRs (PubMed:16803900). Its activity on
CC alpha-3-beta-4/CHRNA3-CHRNB4 nAChR is contreversial, since Talley et
CC al., 2006 report no activity, whereas Ho et al., 2021 report an
CC inhibitory activity (PubMed:16803900, PubMed:34955864).
CC {ECO:0000269|PubMed:16803900, ECO:0000269|PubMed:34955864}.
CC -!- SIMILARITY: Belongs to the conotoxin A superfamily. {ECO:0000305}.
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DR PDB; 2GCZ; NMR; -; A=1-17.
DR PDB; 7N43; X-ray; 2.47 A; F/G/H/I/J=1-17.
DR PDBsum; 2GCZ; -.
DR PDBsum; 7N43; -.
DR AlphaFoldDB; P0C1R7; -.
DR BMRB; P0C1R7; -.
DR SMR; P0C1R7; -.
DR ConoServer; 6; OmIA.
DR EvolutionaryTrace; P0C1R7; -.
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:0099106; F:ion channel regulator activity; IEA:UniProtKB-KW.
DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
DR InterPro; IPR009958; Conotoxin_a-typ.
DR InterPro; IPR018072; Conotoxin_a-typ_CS.
DR Pfam; PF07365; Toxin_8; 1.
DR PROSITE; PS60014; ALPHA_CONOTOXIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylcholine receptor inhibiting toxin; Amidation;
KW Direct protein sequencing; Disulfide bond; Ion channel impairing toxin;
KW Neurotoxin; Postsynaptic neurotoxin; Secreted; Toxin.
FT PEPTIDE 1..17
FT /note="Alpha-conotoxin OmIA"
FT /evidence="ECO:0000269|PubMed:16803900"
FT /id="PRO_0000247849"
FT REGION 4..6
FT /note="Ser-Xaa-Pro motif, crucial for potent interaction
FT with nAChR"
FT /evidence="ECO:0000250|UniProtKB:P56636"
FT SITE 5
FT /note="Key residue for the high potency for alpha-7 nAChRs"
FT /evidence="ECO:0000305|PubMed:34955864"
FT SITE 10
FT /note="Key residue for the high potency for alpha-7 nAChRs"
FT /evidence="ECO:0000305|PubMed:34955864"
FT SITE 11
FT /note="Key residue for the high potency for alpha-7 nAChRs"
FT /evidence="ECO:0000305|PubMed:34955864"
FT MOD_RES 17
FT /note="Glycine amide"
FT /evidence="ECO:0000269|PubMed:16678128,
FT ECO:0000269|PubMed:16803900"
FT DISULFID 2..8
FT /evidence="ECO:0000269|PubMed:16678128,
FT ECO:0000269|PubMed:16803900, ECO:0007744|PDB:2GCZ"
FT DISULFID 3..16
FT /evidence="ECO:0000269|PubMed:16678128,
FT ECO:0000269|PubMed:16803900, ECO:0007744|PDB:2GCZ"
FT MUTAGEN 5
FT /note="H->R: Important decrease in ability to inhibit
FT alpha-7 nAChRs."
FT /evidence="ECO:0000269|PubMed:34955864"
FT MUTAGEN 9
FT /note="N->H: Moderate decrease in ability to inhibit alpha-
FT 7 nAChRs."
FT /evidence="ECO:0000269|PubMed:34955864"
FT MUTAGEN 10
FT /note="V->A: No change in ability to inhibit alpha-7 and
FT alpha-3-beta-4 nAChRs."
FT /evidence="ECO:0000269|PubMed:34955864"
FT MUTAGEN 10
FT /note="V->E: Very important decrease in ability to inhibit
FT alpha-7 nAChRs, and moderate decrease in ability to inhibit
FT alpha-3-beta-4 nAChRs."
FT /evidence="ECO:0000269|PubMed:34955864"
FT MUTAGEN 10
FT /note="V->K: Very important decrease in ability to inhibit
FT alpha-7 nAChRs, and moderate decrease in ability to inhibit
FT alpha-3-beta-4 nAChRs."
FT /evidence="ECO:0000269|PubMed:34955864"
FT MUTAGEN 10
FT /note="V->L: 10-fold increase in ability to inhibit alpha-7
FT nAChRs, and slight decrease in ability to inhibit alpha-3-
FT beta-4 nAChRs."
FT /evidence="ECO:0000269|PubMed:34955864"
FT MUTAGEN 10
FT /note="V->Q: Moderate decrease in ability to inhibit alpha-
FT 7 nAChRs."
FT /evidence="ECO:0000269|PubMed:34955864"
FT MUTAGEN 10
FT /note="V->T: 3.4-fold decrease in ability to inhibit alpha-
FT 7 nAChRs, and moderate decrease in ability to inhibit
FT alpha-3-beta-4 nAChRs."
FT /evidence="ECO:0000269|PubMed:34955864"
FT MUTAGEN 11
FT /note="N->D: Important decrease in ability to inhibit
FT alpha-7 nAChRs."
FT /evidence="ECO:0000269|PubMed:34955864"
FT HELIX 2..4
FT /evidence="ECO:0007829|PDB:7N43"
FT HELIX 6..11
FT /evidence="ECO:0007829|PDB:7N43"
FT TURN 13..15
FT /evidence="ECO:0007829|PDB:7N43"
SQ SEQUENCE 17 AA; 1726 MW; 78963F11BC4AC98F CRC64;
GCCSHPACNV NNPHICG
