O17A_CONMA
ID O17A_CONMA Reviewed; 71 AA.
AC P05484; D6C4G9;
DT 01-NOV-1988, integrated into UniProtKB/Swiss-Prot.
DT 20-JUN-2002, sequence version 2.
DT 25-MAY-2022, entry version 125.
DE RecName: Full=Omega-conotoxin MVIIA {ECO:0000303|PubMed:2441741};
DE AltName: Full=SNX-111;
DE AltName: INN=Ziconotide {ECO:0000303|PubMed:15578997};
DE Flags: Precursor;
OS Conus magus (Magical cone).
OC Eukaryota; Metazoa; Spiralia; Lophotrochozoa; Mollusca; Gastropoda;
OC Caenogastropoda; Neogastropoda; Conoidea; Conidae; Conus; Pionoconus.
OX NCBI_TaxID=6492;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Venom duct;
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 [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=20363338; DOI=10.1016/j.ympev.2010.03.029;
RA Biggs J.S., Watkins M., Puillandre N., Ownby J.P., Lopez-Vera E.,
RA Christensen S., Moreno K.J., Bernaldez J., Licea-Navarro A., Corneli P.S.,
RA Olivera B.M.;
RT "Evolution of Conus peptide toxins: analysis of Conus californicus Reeve,
RT 1844.";
RL Mol. Phylogenet. Evol. 56:1-12(2010).
RN [3]
RP PROTEIN SEQUENCE OF 46-70, AMIDATION AT CYS-70, AND SUBCELLULAR LOCATION.
RC TISSUE=Venom;
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 PROTEIN SEQUENCE OF 46-70, AND SUBCELLULAR LOCATION.
RC TISSUE=Venom;
RX PubMed=2441741; DOI=10.1021/bi00382a004;
RA Olivera B.M., Cruz L.J., de Santos V., Lecheminant G.W., Griffin D.,
RA Zeikus R.D., McIntosh J.M., Galyean R., Varga J., Gray W.R., Rivier J.E.;
RT "Neuronal calcium channel antagonists. Discrimination between calcium
RT channel subtypes using omega-conotoxin from Conus magus venom.";
RL Biochemistry 26:2086-2090(1987).
RN [5]
RP DISULFIDE BONDS.
RX PubMed=8537186; DOI=10.1111/j.1399-3011.1995.tb00604.x;
RA Chung D., Gaur S., Bell J.R., Ramachandran J., Nadasdi L.;
RT "Determination of disulfide bridge pattern in omega-conopeptides.";
RL Int. J. Pept. Protein Res. 46:320-325(1995).
RN [6]
RP FUNCTION, SYNTHESIS OF 46-70, AND MUTAGENESIS OF LYS-47 AND TYR-58.
RX PubMed=7826361; DOI=10.1006/bbrc.1995.1063;
RA Kim J.-I., Takahashi M., Ohtake A., Wakamiya A., Sato K.;
RT "Tyr13 is essential for the activity of omega-conotoxin MVIIA and GVIA,
RT specific N-type calcium channel blockers.";
RL Biochem. Biophys. Res. Commun. 206:449-454(1995).
RN [7]
RP PHARMACEUTICAL USE FOR SEVERE CHRONIC PAIN TREATMENT.
RX PubMed=15578997; DOI=10.2174/0929867043363884;
RA Miljanich G.P.;
RT "Ziconotide: neuronal calcium channel blocker for treating severe chronic
RT pain.";
RL Curr. Med. Chem. 11:3029-3040(2004).
RN [8]
RP FUNCTION, TOXIC DOSE, MUTAGENESIS OF 48-GLY--LYS-52; 56-LEU--ASP-59;
RP LEU-56; MET-57 AND ASP-59, AND BIOASSAY.
RX PubMed=26344359; DOI=10.1016/j.neuropharm.2015.08.047;
RA Wang F., Yan Z., Liu Z., Wang S., Wu Q., Yu S., Ding J., Dai Q.;
RT "Molecular basis of toxicity of N-type calcium channel inhibitor MVIIA.";
RL Neuropharmacology 101:137-145(2016).
RN [9]
RP MUTAGENESIS OF TYR-58.
RC TISSUE=Venom, and Venom duct;
RX PubMed=30194442; DOI=10.1038/s41598-018-31245-4;
RA Sousa S.R., McArthur J.R., Brust A., Bhola R.F., Rosengren K.J.,
RA Ragnarsson L., Dutertre S., Alewood P.F., Christie M.J., Adams D.J.,
RA Vetter I., Lewis R.J.;
RT "Novel analgesic omega-conotoxins from the vermivorous cone snail Conus
RT moncuri provide new insights into the evolution of conopeptides.";
RL Sci. Rep. 8:13397-13397(2018).
RN [10]
RP FUNCTION, AND TOXIC DOSE.
RX PubMed=34589389; DOI=10.1016/j.apsb.2021.03.001;
RA Chen J., Liu X., Yu S., Liu J., Chen R., Zhang Y., Jiang L., Dai Q.;
RT "A novel omega-conotoxin Bu8 inhibiting N-type voltage-gated calcium
RT channels displays potent analgesic activity.";
RL Acta Pharm. Sin. B (APSB) 11:2685-2693(2021).
RN [11]
RP STRUCTURE BY NMR OF 46-70, AND DISULFIDE BONDS.
RX PubMed=7640281; DOI=10.1021/bi00032a020;
RA Kohno T., Kim J.-I., Kobayashi K., Kodera Y., Maeda T., Sato K.;
RT "Three-dimensional structure in solution of the calcium channel blocker
RT omega-conotoxin MVIIA.";
RL Biochemistry 34:10256-10265(1995).
RN [12]
RP STRUCTURE BY NMR OF 46-70, AND DISULFIDE BONDS.
RX PubMed=7656969; DOI=10.1016/0014-5793(95)00819-u;
RA Basus V.J., Nadasdi L., Ramachandran J., Miljanich G.P.;
RT "Solution structure of omega-conotoxin MVIIA using 2D NMR spectroscopy.";
RL FEBS Lett. 370:163-169(1995).
RN [13]
RP STRUCTURE BY NMR OF 46-70, AND DISULFIDE BONDS.
RX PubMed=8913308; DOI=10.1006/jmbi.1996.0576;
RA Nielsen K.J., Thomas L., Lewis R.J., Alewood P.F., Craik D.J.;
RT "A consensus structure for omega-conotoxins with different selectivities
RT for voltage-sensitive calcium channel subtypes: comparison of MVIIA, SVIB
RT and SNX-202.";
RL J. Mol. Biol. 263:297-310(1996).
RN [14]
RP STRUCTURE BY NMR OF 46-70, AND DISULFIDE BONDS.
RX PubMed=10373375; DOI=10.1006/jmbi.1999.2817;
RA Nielsen K.J., Adams D., Thomas L., Bond T., Alewood P.F., Craik D.J.,
RA Lewis R.J.;
RT "Structure-activity relationships of omega-conotoxins MVIIA, MVIIC and 14
RT loop splice hybrids at N and P/Q-type calcium channels.";
RL J. Mol. Biol. 289:1405-1421(1999).
RN [15]
RP STRUCTURE BY NMR OF 46-70, AND DISULFIDE BONDS.
RX PubMed=10747778; DOI=10.1021/bi992651h;
RA Atkinson R.A., Kieffer B., Dejaegere A., Sirockin F., Lefevre J.-F.;
RT "Structural and dynamic characterization of omega-conotoxin MVIIA: the
RT binding loop exhibits slow conformational exchange.";
RL Biochemistry 39:3908-3919(2000).
RN [16]
RP STRUCTURE BY NMR OF 46-70, AND DISULFIDE BONDS.
RX PubMed=11344322; DOI=10.1110/ps.30701;
RA Goldenberg D.P., Koehn R.E., Gilbert D.E., Wagner G.;
RT "Solution structure and backbone dynamics of an omega-conotoxin
RT precursor.";
RL Protein Sci. 10:538-550(2001).
RN [17]
RP STRUCTURE BY ELECTRON MICROSCOPY (3.0 ANGSTROMS) OF 46-70 IN COMPLEX WITH
RP HUMAN CAV2.2/CACNA1B AND SUBUNITS ALPHA2DELTA-1 AND BETA3, FUNCTION,
RP DISULFIDE BOND, AND BINDING SITES TO CAV2.2/CACNA1B.
RX PubMed=34234349; DOI=10.1038/s41586-021-03699-6;
RA Gao S., Yao X., Yan N.;
RT "Structure of human Cav2.2 channel blocked by the painkiller ziconotide.";
RL Nature 596:143-147(2021).
CC -!- FUNCTION: Omega-conotoxins act at presynaptic membranes, they bind and
CC block voltage-gated calcium channels. This toxin blocks Cav2.2/CACNA1B
CC calcium channels (IC(50)=0.67-208 nM) (PubMed:7826361, PubMed:26344359,
CC PubMed:34589389). It acts by neutralizing the outer electronegativity
CC and sterically hindering the ion access path to the entrance of the
CC channel selectivity filter (PubMed:34234349). In vivo, is lethal to
CC fish (PubMed:26344359, PubMed:34589389). In vivo, injection into
CC mammals induces adverse effects, such as tremor, diminution of
CC spontaneous locomotor activity and bad coordinated locomotion
CC (PubMed:26344359). {ECO:0000269|PubMed:26344359,
CC ECO:0000269|PubMed:34234349, ECO:0000269|PubMed:7826361}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:2441741,
CC ECO:0000269|PubMed:4071055}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom duct.
CC {ECO:0000305|PubMed:2441741, ECO:0000305|PubMed:4071055}.
CC -!- DOMAIN: The presence of a 'disulfide through disulfide knot'
CC structurally defines this protein as a knottin.
CC {ECO:0000269|PubMed:10373375, ECO:0000269|PubMed:10747778,
CC ECO:0000269|PubMed:11344322, ECO:0000269|PubMed:7640281,
CC ECO:0000269|PubMed:7656969, ECO:0000269|PubMed:8537186,
CC ECO:0000269|PubMed:8913308}.
CC -!- DOMAIN: The cysteine framework is VI/VII (C-C-CC-C-C). {ECO:0000305}.
CC -!- TOXIC DOSE: LD(50) is 0.10 mg/kg by intramuscular injection into
CC goldfish. {ECO:0000269|PubMed:26344359}.
CC -!- TOXIC DOSE: LD(50) is 0.21 (0.18-0.24) mg/kg by intramuscular injection
CC into goldfish (after 4 hours). {ECO:0000269|PubMed:34589389}.
CC -!- PHARMACEUTICAL: Is available under the names Prialt by Neurex. It
CC blocks acute pain in patients who no longer obtain relief from opiate
CC drugs. It is 100 to 1000 times more potent than morphine. By blocking
CC calcium channels it disable nerves that transmit pain signals.
CC {ECO:0000269|PubMed:15578997}.
CC -!- SIMILARITY: Belongs to the conotoxin O1 superfamily. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Ziconotide Source; Note=Web site on ziconotide;
CC URL="http://www.docmd.com/ziconotide/";
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DR EMBL; FJ959111; ADB93081.1; -; Genomic_DNA.
DR PIR; JH0700; JH0700.
DR PDB; 1DW4; NMR; -; A=46-70.
DR PDB; 1DW5; NMR; -; A=46-70.
DR PDB; 1FEO; NMR; -; A=46-70.
DR PDB; 1MVI; NMR; -; A=46-70.
DR PDB; 1OMG; NMR; -; A=46-70.
DR PDB; 1TT3; NMR; -; A=46-70.
DR PDB; 1TTK; NMR; -; A=46-70.
DR PDB; 7MIX; EM; 3.00 A; B=46-70.
DR PDB; 7VFU; EM; 3.00 A; E=46-70.
DR PDBsum; 1DW4; -.
DR PDBsum; 1DW5; -.
DR PDBsum; 1FEO; -.
DR PDBsum; 1MVI; -.
DR PDBsum; 1OMG; -.
DR PDBsum; 1TT3; -.
DR PDBsum; 1TTK; -.
DR PDBsum; 7MIX; -.
DR PDBsum; 7VFU; -.
DR AlphaFoldDB; P05484; -.
DR SMR; P05484; -.
DR ConoServer; 1564; MVIIA precursor.
DR EvolutionaryTrace; P05484; -.
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; Ion channel impairing toxin;
KW Knottin; Neurotoxin; Pharmaceutical; Presynaptic neurotoxin; Secreted;
KW 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:2441741,
FT ECO:0000269|PubMed:4071055"
FT /id="PRO_0000034914"
FT PEPTIDE 46..70
FT /note="Omega-conotoxin MVIIA"
FT /evidence="ECO:0000269|PubMed:2441741,
FT ECO:0000269|PubMed:4071055"
FT /id="PRO_0000034915"
FT SITE 49
FT /note="Binds Cav2.2/CACNA1B calcium channel"
FT /evidence="ECO:0000269|PubMed:34234349"
FT SITE 55
FT /note="Binds Cav2.2/CACNA1B calcium channel"
FT /evidence="ECO:0000269|PubMed:34234349"
FT SITE 58
FT /note="Binds Cav2.2/CACNA1B calcium channel"
FT /evidence="ECO:0000269|PubMed:30194442,
FT ECO:0000269|PubMed:34234349, ECO:0000269|PubMed:7826361"
FT SITE 62
FT /note="Binds Cav2.2/CACNA1B calcium channel"
FT /evidence="ECO:0000269|PubMed:34234349"
FT SITE 64
FT /note="Binds Cav2.2/CACNA1B calcium channel"
FT /evidence="ECO:0000269|PubMed:34234349"
FT SITE 66
FT /note="Binds Cav2.2/CACNA1B calcium channel"
FT /evidence="ECO:0000269|PubMed:34234349"
FT MOD_RES 70
FT /note="Cysteine amide"
FT /evidence="ECO:0000269|PubMed:2441741"
FT DISULFID 46..61
FT /evidence="ECO:0000269|PubMed:10373375,
FT ECO:0000269|PubMed:10747778, ECO:0000269|PubMed:11344322,
FT ECO:0000269|PubMed:7640281, ECO:0000269|PubMed:7656969,
FT ECO:0000269|PubMed:8537186, ECO:0000269|PubMed:8913308"
FT DISULFID 53..65
FT /evidence="ECO:0000269|PubMed:10373375,
FT ECO:0000269|PubMed:10747778, ECO:0000269|PubMed:11344322,
FT ECO:0000269|PubMed:7640281, ECO:0000269|PubMed:7656969,
FT ECO:0000269|PubMed:8537186, ECO:0000269|PubMed:8913308"
FT DISULFID 60..70
FT /evidence="ECO:0000269|PubMed:10373375,
FT ECO:0000269|PubMed:10747778, ECO:0000269|PubMed:11344322,
FT ECO:0000269|PubMed:7640281, ECO:0000269|PubMed:7656969,
FT ECO:0000269|PubMed:8537186, ECO:0000269|PubMed:8913308"
FT MUTAGEN 47
FT /note="K->A: Little decrease in activity."
FT /evidence="ECO:0000269|PubMed:7826361"
FT MUTAGEN 48..52
FT /note="GKGAK->AAGKP: 4-fold decrease in inhibition of
FT Cav2.2; decrease in efficacy to kill goldfish (LD(50) is
FT 5.20 mg/kg by intramuscular injection) (mutant omega-1)."
FT /evidence="ECO:0000269|PubMed:26344359"
FT MUTAGEN 56..59
FT /note="LMYD->IAYN: 3-fold increase in inhibition of Cav2.2;
FT decrease in efficacy to kill goldfish (LD(50) is 11.6 mg/kg
FT by intramuscular injection) (mutant omega-2)."
FT /evidence="ECO:0000269|PubMed:26344359"
FT MUTAGEN 56
FT /note="L->I: 1.8-fold decrease in inhibition of Cav2.2;
FT decrease in efficacy to kill goldfish (LD(50) is 0.93 mg/kg
FT by intramuscular injection) (mutant omega-5)."
FT /evidence="ECO:0000269|PubMed:26344359"
FT MUTAGEN 57
FT /note="M->A: 2.11-fold decrease in inhibition of Cav2.2;
FT decrease in efficacy to kill goldfish (LD(50) is 1.80 mg/kg
FT by intramuscular injection) (mutant omega-4)."
FT /evidence="ECO:0000269|PubMed:26344359"
FT MUTAGEN 58
FT /note="Y->A: Strong decrease in activity."
FT /evidence="ECO:0000269|PubMed:7826361"
FT MUTAGEN 58
FT /note="Y->R: Loss of inhibition of human Cav2.2/CACNA1B."
FT /evidence="ECO:0000269|PubMed:30194442"
FT MUTAGEN 59
FT /note="D->N: 2.8-fold increase in inhibition of Cav2.2;
FT decrease in efficacy to kill goldfish (LD(50) is 0.20 mg/kg
FT by intramuscular injection) (mutant omega-3)."
FT /evidence="ECO:0000269|PubMed:26344359"
FT CONFLICT 42
FT /note="T -> M (in Ref. 2; ADB93081)"
FT /evidence="ECO:0000305"
FT HELIX 55..57
FT /evidence="ECO:0007829|PDB:7MIX"
FT STRAND 60..63
FT /evidence="ECO:0007829|PDB:7MIX"
SQ SEQUENCE 71 AA; 7587 MW; E2A32725C81AF31D CRC64;
MKLTCVVIVA VLLLTACQLI TADDSRGTQK HRALRSTTKL STSTRCKGKG AKCSRLMYDC
CTGSCRSGKC G
