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 22-FEB-2023, entry version 131. 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}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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:0044231; C:host cell presynaptic membrane; IEA:UniProtKB-KW. 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 SUPFAM; SSF57059; omega toxin-like; 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 //