O17A_CONPU
ID O17A_CONPU Reviewed; 72 AA.
AC P56633;
DT 15-DEC-1998, integrated into UniProtKB/Swiss-Prot.
DT 26-JUL-2002, sequence version 2.
DT 25-MAY-2022, entry version 108.
DE RecName: Full=Kappa-conotoxin PVIIA {ECO:0000303|PubMed:12074021, ECO:0000303|PubMed:9417043, ECO:0000303|PubMed:9438859, ECO:0000303|PubMed:9548922};
DE AltName: Full=CGX-1051 {ECO:0000303|PubMed:16044024};
DE AltName: Full=Fin-popping peptide {ECO:0000303|PubMed:12074021, ECO:0000303|PubMed:9417043};
DE Flags: Precursor;
OS Conus purpurascens (Purple cone).
OC Eukaryota; Metazoa; Spiralia; Lophotrochozoa; Mollusca; Gastropoda;
OC Caenogastropoda; Neogastropoda; Conoidea; Conidae; Conus; Chelyconus.
OX NCBI_TaxID=41690;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], SYNTHESIS OF 46-72, FUNCTION, MASS
RP SPECTROMETRY, DISULFIDE BOND, SUBCELLULAR LOCATION, AND BIOASSAY.
RC TISSUE=Venom, and Venom duct;
RX PubMed=9417043; DOI=10.1074/jbc.273.1.33;
RA Shon K.-J., Stocker M., Terlau H., Stuehmer W., Jacobsen R.B., Walker C.S.,
RA Grilley M.M., Watkins M., Hillyard D.R., Gray W.R., Olivera B.M.;
RT "Kappa-conotoxin PVIIA is a peptide inhibiting the shaker K+ channel.";
RL J. Biol. Chem. 273:33-38(1998).
RN [2]
RP PROTEIN SEQUENCE OF 46-72, FUNCTION, HYDROXYLATION AT PRO-49, SYNTHESIS OF
RP 46-72, AND BIOASSAY.
RX PubMed=12074021; DOI=10.1038/381148a0;
RA Terlau H., Shon K.-J., Grilley M.M., Stocker M., Stuehmer W., Olivera B.M.;
RT "Strategy for rapid immobilization of prey by a fish-hunting marine
RT snail.";
RL Nature 381:148-151(1996).
RN [3]
RP FUNCTION.
RX PubMed=10398696; DOI=10.1085/jgp.114.1.125;
RA Terlau H., Boccaccio A., Olivera B.M., Conti F.;
RT "The block of Shaker K+ channels by kappa-conotoxin PVIIA is state
RT dependent.";
RL J. Gen. Physiol. 114:125-140(1999).
RN [4]
RP MUTAGENESIS OF ARG-47; ILE-48; PRO-49; ASN-50; GLN-51; LYS-52; PHE-54;
RP PHE-54; GLN-55; HIS-56; LEU-57; ASP-58; ASP-59; SER-62; ARG-63; LYS-64;
RP ARG-67; PHE-68; ASN-69 AND LYS-70.
RX PubMed=10818087; DOI=10.1074/jbc.c900990199;
RA Jacobsen R.B., Koch E.D., Lange-Malecki B., Stocker M., Verhey J.,
RA Van Wagoner R.M., Vyazovkina A., Olivera B.M., Terlau H.;
RT "Single amino acid substitutions in kappa-conotoxin PVIIA disrupt
RT interaction with the shaker K+ channel.";
RL J. Biol. Chem. 275:24639-24644(2000).
RN [5]
RP 3D-STRUCTURE MODELING OF THE SHAKER-PVIIA INTERACTION.
RX PubMed=11820396; DOI=10.1007/s00249-001-0189-8;
RA Moran O.;
RT "Molecular simulation of the interaction of kappa-conotoxin-PVIIA with the
RT Shaker potassium channel pore.";
RL Eur. Biophys. J. 30:528-536(2001).
RN [6]
RP FUNCTION.
RX PubMed=12023223; DOI=10.1016/s0006-3495(02)75641-5;
RA Naranjo D.;
RT "Inhibition of single Shaker K channels by kappa-conotoxin-PVIIA.";
RL Biophys. J. 82:3003-3011(2002).
RN [7]
RP FUNCTION, AND MOLECULAR DYNAMICS SIMULATIONS.
RX PubMed=15869307; DOI=10.1021/ja042641q;
RA Huang X., Dong F., Zhou H.X.;
RT "Electrostatic recognition and induced fit in the kappa-PVIIA toxin binding
RT to Shaker potassium channel.";
RL J. Am. Chem. Soc. 127:6836-6849(2005).
RN [8]
RP PHARMACEUTICAL.
RX PubMed=16044024; DOI=10.1097/01.fjc.0000167015.84715.27;
RA Lubbers N.L., Campbell T.J., Polakowski J.S., Bulaj G., Layer R.T.,
RA Moore J., Gross G.J., Cox B.F.;
RT "Postischemic administration of CGX-1051, a peptide from cone snail venom,
RT reduces infarct size in both rat and dog models of myocardial ischemia and
RT reperfusion.";
RL J. Cardiovasc. Pharmacol. 46:141-146(2005).
RN [9]
RP FUNCTION, AND MOLECULAR DYNAMICS SIMULATIONS.
RX PubMed=23398369; DOI=10.1021/bi301257p;
RA Mahdavi S., Kuyucak S.;
RT "Why the Drosophila Shaker K+ channel is not a good model for ligand
RT binding to voltage-gated Kv1 channels.";
RL Biochemistry 52:1631-1640(2013).
RN [10]
RP STRUCTURE BY NMR OF SYNTHETIC CYCLIC PVIIA, FUNCTION, AND MUTAGENESIS OF
RP VAL-72.
RX PubMed=27093300; DOI=10.1002/bit.25993;
RA Kwon S., Bosmans F., Kaas Q., Cheneval O., Conibear A.C., Rosengren K.J.,
RA Wang C.K., Schroeder C.I., Craik D.J.;
RT "Efficient enzymatic cyclization of an inhibitory cystine knot-containing
RT peptide.";
RL Biotechnol. Bioeng. 113:2202-2212(2016).
RN [11]
RP STRUCTURE BY NMR OF 46-72, DISULFIDE BONDS, AND SYNTHESIS OF 46-72.
RC TISSUE=Venom;
RX PubMed=9438859; DOI=10.1016/s0969-2126(97)00307-9;
RA Scanlon M.J., Naranjo D., Thomas L., Alewood P.F., Lewis R.J., Craik D.J.;
RT "Solution structure and proposed binding mechanism of a novel potassium
RT channel toxin kappa-conotoxin PVIIA.";
RL Structure 5:1585-1597(1997).
RN [12]
RP STRUCTURE BY NMR OF 46-72, DISULFIDE BONDS, AND SYNTHESIS OF 46-72.
RX PubMed=9548922; DOI=10.1021/bi9730341;
RA Savarin P., Guenneugues M., Gilquin B., Lamthanh H., Gasparini S.,
RA Zinn-Justin S., Menez A.;
RT "Three-dimensional structure of kappa-conotoxin PVIIA, a novel potassium
RT channel-blocking toxin from cone snails.";
RL Biochemistry 37:5407-5416(1998).
CC -!- FUNCTION: Kappa-conotoxins bind and inhibit voltage-gated potassium
CC channels (Kv). This toxin inhibits the drosophila Shaker channel
CC (IC(50)=57-80 nM) (PubMed:12074021, PubMed:10818087, PubMed:27093300).
CC In vivo, when tested in fish, this toxin induces hyperactivity,
CC followed by continuous contraction and extension of major fins, without
CC immobilization or death (PubMed:9417043, PubMed:12074021). Injection of
CC this peptide together with the delta-conotoxin PVIA causes the sudden
CC tetanus of prey (STOP) syndrome, which is a single, lethal 'fin-pop' in
CC envenomed fish (PubMed:9417043, PubMed:12074021). When tested in mice,
CC induces hyperactivity (PubMed:9417043). {ECO:0000269|PubMed:10398696,
CC ECO:0000269|PubMed:10818087, ECO:0000269|PubMed:12023223,
CC ECO:0000269|PubMed:12074021, ECO:0000269|PubMed:27093300,
CC ECO:0000269|PubMed:9417043}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:9417043}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom duct.
CC {ECO:0000305|PubMed:9417043}.
CC -!- DOMAIN: The presence of a 'disulfide through disulfide knot'
CC structurally defines this protein as a knottin.
CC {ECO:0000269|PubMed:9417043, ECO:0000269|PubMed:9438859,
CC ECO:0000269|PubMed:9548922}.
CC -!- DOMAIN: The cysteine framework is VI/VII (C-C-CC-C-C). {ECO:0000305}.
CC -!- PTM: This toxin is not amidated at the C-terminal Val residue.
CC {ECO:0000269|PubMed:9417043, ECO:0000269|PubMed:9438859}.
CC -!- MASS SPECTROMETRY: Mass=3268.4; Method=FAB; Note=Monoisotopic mass.;
CC Evidence={ECO:0000269|PubMed:9417043};
CC -!- PHARMACEUTICAL: Was tested under preclinical trial by Cognetix Inc
CC under the name CGX-1051 as a cardioprotective agent.
CC {ECO:0000305|PubMed:16044024}.
CC -!- MISCELLANEOUS: A free N-terminal residue (not acetylated or not
CC cyclizated) is necessary for optimal inhibition of Shaker potassium
CC channel. {ECO:0000269|PubMed:27093300}.
CC -!- MISCELLANEOUS: This toxin has no effect on the rat Kv1.1/KCNA1 channel
CC (PubMed:9417043). Does not inhibit Kv1.3/KCNA3, Kv1.6/KCNA6,
CC Kv2.1/KCNB1, Nav1.4/SCN4A and Nav1.6/SCN8A (PubMed:27093300).
CC {ECO:0000269|PubMed:27093300, ECO:0000269|PubMed:9417043}.
CC -!- SIMILARITY: Belongs to the conotoxin O1 superfamily. {ECO:0000305}.
CC -!- CAUTION: Because analogs resulting of mutagenesis of Hyp-49, Asn-50,
CC Leu-57 and Asp-59 give very low yields upon folding, the results of
CC mutagenesis on these residues should be interpreted with caution.
CC {ECO:0000305}.
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DR PIR; A58997; A58997.
DR PDB; 1AV3; NMR; -; A=46-72.
DR PDB; 1KCP; NMR; -; A=46-72.
DR PDB; 2N8E; NMR; -; A=46-72.
DR PDBsum; 1AV3; -.
DR PDBsum; 1KCP; -.
DR PDBsum; 2N8E; -.
DR AlphaFoldDB; P56633; -.
DR BMRB; P56633; -.
DR SMR; P56633; -.
DR ConoServer; 1331; PVIIA precursor.
DR EvolutionaryTrace; P56633; -.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0008200; F:ion channel inhibitor activity; IEA:InterPro.
DR GO; GO:0015459; F:potassium channel regulator activity; IEA:UniProtKB-KW.
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 3D-structure; Direct protein sequencing; Disulfide bond; Hydroxylation;
KW Ion channel impairing toxin; Knottin; Neurotoxin; Pharmaceutical;
KW Potassium channel impairing toxin; Secreted; Signal; Toxin;
KW Voltage-gated potassium channel impairing toxin.
FT SIGNAL 1..22
FT /evidence="ECO:0000255"
FT PROPEP 23..45
FT /evidence="ECO:0000269|PubMed:12074021"
FT /id="PRO_0000034981"
FT PEPTIDE 46..72
FT /note="Kappa-conotoxin PVIIA"
FT /evidence="ECO:0000269|PubMed:12074021"
FT /id="PRO_0000034982"
FT SITE 52
FT /note="Inserts into the pore of the channel and blocks the
FT flow of potassium ions"
FT /evidence="ECO:0000305|PubMed:10818087,
FT ECO:0000305|PubMed:15869307, ECO:0000305|PubMed:23398369"
FT MOD_RES 49
FT /note="4-hydroxyproline"
FT /evidence="ECO:0000269|PubMed:12074021"
FT DISULFID 46..61
FT /evidence="ECO:0000269|PubMed:9417043,
FT ECO:0000269|PubMed:9438859, ECO:0000269|PubMed:9548922,
FT ECO:0000312|PDB:1AV3, ECO:0000312|PDB:1KCP,
FT ECO:0000312|PDB:2N8E"
FT DISULFID 53..65
FT /evidence="ECO:0000269|PubMed:9417043,
FT ECO:0000269|PubMed:9438859, ECO:0000269|PubMed:9548922,
FT ECO:0000312|PDB:1AV3, ECO:0000312|PDB:1KCP,
FT ECO:0000312|PDB:2N8E"
FT DISULFID 60..71
FT /evidence="ECO:0000269|PubMed:9417043,
FT ECO:0000269|PubMed:9438859, ECO:0000269|PubMed:9548922,
FT ECO:0000312|PDB:1AV3, ECO:0000312|PDB:1KCP,
FT ECO:0000312|PDB:2N8E"
FT MUTAGEN 47
FT /note="R->A,K,Q: Loss of toxicity."
FT /evidence="ECO:0000269|PubMed:10818087"
FT MUTAGEN 48
FT /note="I->A: 3-fold decrease of toxicity."
FT /evidence="ECO:0000269|PubMed:10818087"
FT MUTAGEN 49
FT /note="P->A: Loss of toxicity."
FT /evidence="ECO:0000269|PubMed:10818087"
FT MUTAGEN 50
FT /note="N->A: Loss of toxicity."
FT /evidence="ECO:0000269|PubMed:10818087"
FT MUTAGEN 51
FT /note="Q->A: 13-fold decrease of toxicity."
FT /evidence="ECO:0000269|PubMed:10818087"
FT MUTAGEN 52
FT /note="K->A,R: Loss of toxicity."
FT /evidence="ECO:0000269|PubMed:10818087"
FT MUTAGEN 54
FT /note="F->A,M: Loss of toxicity."
FT /evidence="ECO:0000269|PubMed:10818087"
FT MUTAGEN 54
FT /note="F->Y: 11-fold decrease of toxicity."
FT /evidence="ECO:0000269|PubMed:10818087"
FT MUTAGEN 55
FT /note="Q->A: 3-fold decrease of toxicity."
FT /evidence="ECO:0000269|PubMed:10818087"
FT MUTAGEN 56
FT /note="H->A: 3-fold decrease of toxicity."
FT /evidence="ECO:0000269|PubMed:10818087"
FT MUTAGEN 57
FT /note="L->A: Loss of toxicity."
FT /evidence="ECO:0000269|PubMed:10818087"
FT MUTAGEN 58
FT /note="D->A: 1.5-fold decrease of toxicity."
FT /evidence="ECO:0000269|PubMed:10818087"
FT MUTAGEN 59
FT /note="D->A: Loss of toxicity."
FT /evidence="ECO:0000269|PubMed:10818087"
FT MUTAGEN 62
FT /note="S->A: 1.5-fold decrease of toxicity."
FT /evidence="ECO:0000269|PubMed:10818087"
FT MUTAGEN 63
FT /note="R->A: 3.5-fold decrease of toxicity."
FT /evidence="ECO:0000269|PubMed:10818087"
FT MUTAGEN 64
FT /note="K->A: 1.2-fold decrease of toxicity."
FT /evidence="ECO:0000269|PubMed:10818087"
FT MUTAGEN 67
FT /note="R->A: 5-fold decrease of toxicity."
FT /evidence="ECO:0000269|PubMed:10818087"
FT MUTAGEN 68
FT /note="F->A: 17-fold decrease of toxicity."
FT /evidence="ECO:0000269|PubMed:10818087"
FT MUTAGEN 69
FT /note="N->A: 19-fold decrease of toxicity."
FT /evidence="ECO:0000269|PubMed:10818087"
FT MUTAGEN 70
FT /note="K->A: 117-fold decrease of toxicity."
FT /evidence="ECO:0000269|PubMed:10818087"
FT MUTAGEN 72
FT /note="V->VLPETGGG: Cyclic-[GGG]PVIIA[LPET]; 10-fold
FT decrease in ability to inhibit Shaker potassium channel,
FT and decrease in serum stability."
FT /evidence="ECO:0000269|PubMed:27093300"
FT HELIX 55..57
FT /evidence="ECO:0007829|PDB:1AV3"
FT STRAND 60..62
FT /evidence="ECO:0007829|PDB:1AV3"
FT STRAND 69..71
FT /evidence="ECO:0007829|PDB:1AV3"
SQ SEQUENCE 72 AA; 8317 MW; 53BFAF79EE751C16 CRC64;
MKLTCVVIVV VLFLTACQLI TADDSRRTQK HRALRSTTKL SLSTRCRIPN QKCFQHLDDC
CSRKCNRFNK CV
