O16A_CONGE
ID O16A_CONGE Reviewed; 73 AA.
AC P01522;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1994, sequence version 2.
DT 25-MAY-2022, entry version 129.
DE RecName: Full=Omega-conotoxin GVIA {ECO:0000303|PubMed:6509012};
DE AltName: Full=SNX-124;
DE AltName: Full=Shaker peptide {ECO:0000303|PubMed:6509012};
DE Contains:
DE RecName: Full=Omega-conotoxin GVIB {ECO:0000303|PubMed:4071055};
DE Contains:
DE RecName: Full=Omega-conotoxin GVIC {ECO:0000303|PubMed:4071055};
DE Flags: Precursor;
OS Conus geographus (Geography cone) (Nubecula geographus).
OC Eukaryota; Metazoa; Spiralia; Lophotrochozoa; Mollusca; Gastropoda;
OC Caenogastropoda; Neogastropoda; Conoidea; Conidae; Conus; Gastridium.
OX NCBI_TaxID=6491;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=1440648; DOI=10.1016/0041-0101(92)90056-b;
RA Colledge C.J., Hunsperger J.P., Imperial J.S., Hillyard D.R.;
RT "Precursor structure of omega-conotoxin GVIA determined from a cDNA
RT clone.";
RL Toxicon 30:1111-1116(1992).
RN [2]
RP PROTEIN SEQUENCE OF 46-72 (GVIA), HYDROXYLATION AT PRO-49; PRO-55 AND
RP PRO-66, AND AMIDATION AT TYR-72.
RX PubMed=6509012; DOI=10.1021/bi00317a001;
RA Olivera B.M., McIntosh J.M., Cruz L.J., Luque F.A., Gray W.R.;
RT "Purification and sequence of a presynaptic peptide toxin from Conus
RT geographus venom.";
RL Biochemistry 23:5087-5090(1984).
RN [3]
RP PROTEIN SEQUENCE OF 46-73 (GVIB AND GVIC).
RX PubMed=4071055; DOI=10.1126/science.4071055;
RA Olivera B.M., Gray W.R., Zeikus R.D., McIntosh J.M., Varga J., Rivier J.E.,
RA de Santos V., Cruz L.J.;
RT "Peptide neurotoxins from fish-hunting cone snails.";
RL Science 230:1338-1343(1985).
RN [4]
RP SYNTHESIS OF 46-72 (GVIA), AND DISULFIDE BONDS.
RX PubMed=3779030;
RA Nishiuchi Y., Kumagaye K., Noda Y., Watanabe T.X., Sakakibara S.;
RT "Synthesis and secondary-structure determination of omega-conotoxin GVIA: a
RT 27-peptide with three intramolecular disulfide bonds.";
RL Biopolymers 25:S61-S68(1986).
RN [5]
RP MUTAGENESIS OF LYS-47; ARG-62; LYS-69 AND ARG-70.
RX PubMed=8394704; DOI=10.1006/bbrc.1993.1964;
RA Sato K., Park N.G., Kohno T., Maeda T., Kim J.-I., Kato R., Takahashi M.;
RT "Role of basic residues for the binding of omega-conotoxin GVIA to N-type
RT calcium channels.";
RL Biochem. Biophys. Res. Commun. 194:1292-1296(1993).
RN [6]
RP MUTAGENESIS OF TYR-58.
RX PubMed=7929033; DOI=10.1016/s0021-9258(19)51019-5;
RA Kim J.-I., Takahashi M., Ogura A., Kohno T., Kudo Y., Sato K.;
RT "Hydroxyl group of Tyr13 is essential for the activity of omega-conotoxin
RT GVIA, a peptide toxin for N-type calcium channel.";
RL J. Biol. Chem. 269:23876-23878(1994).
RN [7]
RP SYNTHESIS OF 46-72 (GVIA), MUTAGENESIS OF LYS-47; TYR-58; ARG-62; TYR-67
RP AND LYS-69, AND STRUCTURE BY NMR OF 46-72 (GVIA).
RX PubMed=9115267; DOI=10.1074/jbc.272.18.12014;
RA Lew M.J., Flinn J.P., Pallaghy P.K., Murphy R., Whorlow S.L., Wright C.E.,
RA Norton R.S., Angus J.A.;
RT "Structure-function relationships of omega-conotoxin GVIA. Synthesis,
RT structure, calcium channel binding, and functional assay of alanine-
RT substituted analogues.";
RL J. Biol. Chem. 272:12014-12023(1997).
RN [8]
RP FUNCTION, AND SYNTHESIS OF 46-72 (GVIA).
RX PubMed=10938268; DOI=10.1074/jbc.m002252200;
RA Lewis R.J., Nielsen K.J., Craik D.J., Loughnan M.L., Adams D.A.,
RA Sharpe I.A., Luchian T., Adams D.J., Bond T., Thomas L., Jones A.,
RA Matheson J.-L., Drinkwater R., Andrews P.R., Alewood P.F.;
RT "Novel omega-conotoxins from Conus catus discriminate among neuronal
RT calcium channel subtypes.";
RL J. Biol. Chem. 275:35335-35344(2000).
RN [9]
RP FUNCTION, AND SYNTHESIS OF 46-72 (GVIA).
RX PubMed=11724570; DOI=10.1021/bi002871r;
RA Favreau P., Gilles N., Lamthanh H., Bournaud R., Shimahara T., Bouet F.,
RA Laboute P., Letourneux Y., Menez A., Molgo J., Le Gall F.;
RT "A new omega-conotoxin that targets N-type voltage-sensitive calcium
RT channels with unusual specificity.";
RL Biochemistry 40:14567-14575(2001).
RN [10]
RP STRUCTURE BY NMR OF 46-72 (GVIA), AND DISULFIDE BONDS.
RX PubMed=8343203; DOI=10.1006/bbrc.1993.1549;
RA Sevilla P., Bruix M., Santoro J., Gago F., Garcia A.G., Rico M.;
RT "Three-dimensional structure of omega-conotoxin GVIA determined by 1H
RT NMR.";
RL Biochem. Biophys. Res. Commun. 192:1238-1244(1993).
RN [11]
RP STRUCTURE BY NMR OF 46-72 (GVIA), AND DISULFIDE BONDS.
RX PubMed=8338837; DOI=10.1021/bi00080a009;
RA Davis J.H., Bradley E.K., Miljanich G.P., Nadasdi L., Ramachandran J.,
RA Basus V.J.;
RT "Solution structure of omega-conotoxin GVIA using 2-D NMR spectroscopy and
RT relaxation matrix analysis.";
RL Biochemistry 32:7396-7405(1993).
RN [12]
RP STRUCTURE BY NMR OF 46-72 (GVIA), AND DISULFIDE BONDS.
RX PubMed=8230223; DOI=10.1006/jmbi.1993.1595;
RA Pallaghy P.K., Duggan B.M., Pennington M.W., Norton R.S.;
RT "Three-dimensional structure in solution of the calcium channel blocker
RT omega-conotoxin.";
RL J. Mol. Biol. 234:405-420(1993).
RN [13]
RP STRUCTURE BY NMR OF 46-72 (GVIA), AND DISULFIDE BONDS.
RX PubMed=8251934; DOI=10.1002/pro.5560021005;
RA Skalicky J.J., Metzler W.J., Ciesla D.J., Galdes A., Pardi A.;
RT "Solution structure of the calcium channel antagonist omega-conotoxin
RT GVIA.";
RL Protein Sci. 2:1591-1603(1993).
RN [14]
RP STRUCTURE BY NMR OF 46-72 (GVIA), AND DISULFIDE BONDS.
RX PubMed=10231724; DOI=10.1034/j.1399-3011.1999.00040.x;
RA Pallaghy P.K., Norton R.S.;
RT "Refined solution structure of omega-conotoxin GVIA: implications for
RT calcium channel binding.";
RL J. Pept. Res. 53:343-351(1999).
RN [15]
RP REVIEW.
RX PubMed=10822250;
RX DOI=10.1002/(sici)1099-1352(200003/04)13:2<55::aid-jmr488>3.0.co;2-o;
RA Nielsen K.J., Schroeder T., Lewis R.J.;
RT "Structure-activity relationships of omega-conotoxins at N-type voltage-
RT sensitive calcium channels.";
RL J. Mol. Recognit. 13:55-70(2000).
CC -!- FUNCTION: [Omega-conotoxin GVIA]: Omega-conotoxins act at presynaptic
CC membranes, they bind and block voltage-gated calcium channels (Cav).
CC This toxin blocks N-type calcium channels (Cav2.2/CACNA1B) with a high
CC potency (it displaces [125I]GVIA with an IC(50)=3.7-38 pM)
CC (PubMed:10938268, PubMed:11724570). {ECO:0000269|PubMed:10938268,
CC ECO:0000269|PubMed:11724570}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:6509012}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom duct.
CC {ECO:0000305|PubMed:6509012}.
CC -!- DOMAIN: The presence of a 'disulfide through disulfide knot'
CC structurally defines this protein as a knottin.
CC {ECO:0000269|PubMed:10231724, ECO:0000269|PubMed:8230223,
CC ECO:0000269|PubMed:8251934, ECO:0000269|PubMed:8338837,
CC ECO:0000269|PubMed:8343203}.
CC -!- DOMAIN: The cysteine framework is VI/VII (C-C-CC-C-C). {ECO:0000305}.
CC -!- MISCELLANEOUS: Has a very low activity on Cav2.1 (it displaces
CC [125I]MVIIC with an IC(50)=1.05 uM) (PubMed:10938268).
CC {ECO:0000269|PubMed:10938268}.
CC -!- SIMILARITY: Belongs to the conotoxin O1 superfamily. {ECO:0000305}.
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DR EMBL; M84612; AAA81590.1; -; mRNA.
DR PIR; A44006; NTKN6G.
DR PDB; 1OMC; NMR; -; A=46-72.
DR PDB; 1TR6; NMR; -; A=46-72.
DR PDB; 1TTL; NMR; -; A=46-72.
DR PDB; 2CCO; NMR; -; A=46-72.
DR PDBsum; 1OMC; -.
DR PDBsum; 1TR6; -.
DR PDBsum; 1TTL; -.
DR PDBsum; 2CCO; -.
DR AlphaFoldDB; P01522; -.
DR SMR; P01522; -.
DR IntAct; P01522; 1.
DR ConoServer; 820; GVIA precursor.
DR EvolutionaryTrace; P01522; -.
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:0090729; F:toxin activity; IEA:UniProtKB-KW.
DR InterPro; IPR004214; Conotoxin.
DR InterPro; IPR012321; Conotoxin_omega-typ_CS.
DR Pfam; PF02950; Conotoxin; 1.
DR PROSITE; PS60004; OMEGA_CONOTOXIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Amidation; Calcium channel impairing toxin;
KW Direct protein sequencing; Disulfide bond; Hydroxylation;
KW Ion channel impairing toxin; Knottin; Neurotoxin; Presynaptic neurotoxin;
KW Secreted; Signal; Toxin; Voltage-gated calcium channel impairing toxin.
FT SIGNAL 1..22
FT /evidence="ECO:0000255"
FT PROPEP 23..45
FT /evidence="ECO:0000269|PubMed:4071055,
FT ECO:0000269|PubMed:6509012"
FT /id="PRO_0000034906"
FT PEPTIDE 46..73
FT /note="Omega-conotoxin GVIB"
FT /evidence="ECO:0000269|PubMed:4071055"
FT /id="PRO_0000034907"
FT PEPTIDE 46..72
FT /note="Omega-conotoxin GVIA"
FT /evidence="ECO:0000269|PubMed:6509012"
FT /id="PRO_0000034908"
FT PEPTIDE 46..71
FT /note="Omega-conotoxin GVIC"
FT /evidence="ECO:0000269|PubMed:4071055"
FT /id="PRO_0000034909"
FT MOD_RES 49
FT /note="4-hydroxyproline"
FT /evidence="ECO:0000269|PubMed:6509012"
FT MOD_RES 55
FT /note="4-hydroxyproline"
FT /evidence="ECO:0000269|PubMed:6509012"
FT MOD_RES 66
FT /note="4-hydroxyproline"
FT /evidence="ECO:0000269|PubMed:6509012"
FT MOD_RES 72
FT /note="Tyrosine amide; in form omega-conotoxin GVIA"
FT /evidence="ECO:0000269|PubMed:6509012"
FT DISULFID 46..61
FT /evidence="ECO:0000269|PubMed:10231724,
FT ECO:0000269|PubMed:8230223, ECO:0000269|PubMed:8251934,
FT ECO:0000269|PubMed:8338837, ECO:0000269|PubMed:8343203,
FT ECO:0000312|PDB:1OMC, ECO:0000312|PDB:1TR6,
FT ECO:0000312|PDB:1TTL, ECO:0000312|PDB:2CCO"
FT DISULFID 53..64
FT /evidence="ECO:0000269|PubMed:10231724,
FT ECO:0000269|PubMed:8230223, ECO:0000269|PubMed:8251934,
FT ECO:0000269|PubMed:8338837, ECO:0000269|PubMed:8343203,
FT ECO:0000312|PDB:1OMC, ECO:0000312|PDB:1TR6,
FT ECO:0000312|PDB:1TTL, ECO:0000312|PDB:2CCO"
FT DISULFID 60..71
FT /evidence="ECO:0000269|PubMed:10231724,
FT ECO:0000269|PubMed:8230223, ECO:0000269|PubMed:8251934,
FT ECO:0000269|PubMed:8338837, ECO:0000269|PubMed:8343203,
FT ECO:0000312|PDB:1OMC, ECO:0000312|PDB:1TR6,
FT ECO:0000312|PDB:1TTL, ECO:0000312|PDB:2CCO"
FT MUTAGEN 47
FT /note="K->A: Strong decrease in activity."
FT /evidence="ECO:0000269|PubMed:8394704,
FT ECO:0000269|PubMed:9115267"
FT MUTAGEN 58
FT /note="Y->A: Strong decrease in activity."
FT /evidence="ECO:0000269|PubMed:7929033,
FT ECO:0000269|PubMed:9115267"
FT MUTAGEN 58
FT /note="Y->F: Decrease in affinity."
FT /evidence="ECO:0000269|PubMed:7929033,
FT ECO:0000269|PubMed:9115267"
FT MUTAGEN 62
FT /note="R->A: Decrease in potency, but not in affinity."
FT /evidence="ECO:0000269|PubMed:8394704,
FT ECO:0000269|PubMed:9115267"
FT MUTAGEN 67
FT /note="Y->A: Decrease in potency, but not in affinity."
FT /evidence="ECO:0000269|PubMed:9115267"
FT MUTAGEN 69
FT /note="K->A: Decrease in potency, but not in affinity."
FT /evidence="ECO:0000269|PubMed:8394704,
FT ECO:0000269|PubMed:9115267"
FT MUTAGEN 70
FT /note="R->A: No change in activity."
FT /evidence="ECO:0000269|PubMed:8394704"
FT TURN 55..58
FT /evidence="ECO:0007829|PDB:1OMC"
FT STRAND 60..62
FT /evidence="ECO:0007829|PDB:1OMC"
FT TURN 66..68
FT /evidence="ECO:0007829|PDB:1OMC"
FT STRAND 69..71
FT /evidence="ECO:0007829|PDB:1OMC"
SQ SEQUENCE 73 AA; 7851 MW; 51A8C8FA630F7175 CRC64;
MKLTCVVIVA VLLLTACQLI TADDSRGTQK HRALGSTTEL SLSTRCKSPG SSCSPTSYNC
CRSCNPYTKR CYG
