CKG_CONGE
ID CKG_CONGE Reviewed; 100 AA.
AC P07231; O61475;
DT 01-APR-1988, integrated into UniProtKB/Swiss-Prot.
DT 15-DEC-1998, sequence version 2.
DT 03-AUG-2022, entry version 120.
DE RecName: Full=Conantokin-G {ECO:0000303|PubMed:8999936};
DE Short=Con-G {ECO:0000303|PubMed:8999936};
DE AltName: Full=CGX-1007;
DE AltName: Full=Conotoxin GV {ECO:0000303|PubMed:6501296};
DE AltName: Full=Sleeper peptide {ECO:0000303|PubMed:6501296};
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], AND VARIANT VAL-85.
RC TISSUE=Venom duct;
RX PubMed=9488665; DOI=10.1074/jbc.273.10.5447;
RA Bandyopadhyay P.K., Colledge C.J., Walker C.S., Zhou L.-M., Hillyard D.R.,
RA Olivera B.M.;
RT "Conantokin-G precursor and its role in gamma-carboxylation by a vitamin K-
RT dependent carboxylase from a Conus snail.";
RL J. Biol. Chem. 273:5447-5450(1998).
RN [2]
RP PROTEIN SEQUENCE OF 81-97, AMIDATION AT ASN-97, GAMMA-CARBOXYGLUTAMATION AT
RP GLU-83; GLU-84; GLU-87; GLU-90 AND GLU-94, AND SUBCELLULAR LOCATION.
RC TISSUE=Venom;
RX PubMed=6501296; DOI=10.1016/s0021-9258(17)42601-9;
RA McIntosh J.M., Olivera B.M., Cruz L.J., Gray W.R.;
RT "Gamma-carboxyglutamate in a neuroactive toxin.";
RL J. Biol. Chem. 259:14343-14346(1984).
RN [3]
RP FUNCTION.
RX PubMed=2165278; DOI=10.1126/science.2165278;
RA Olivera B.M., Rivier J., Clark C., Ramilo C.A., Corpuz G.P., Abogadie F.C.,
RA Mena E.E., Woodward S.R., Hillyard D.R., Cruz L.J.;
RT "Diversity of Conus neuropeptides.";
RL Science 249:257-263(1990).
RN [4]
RP MUTAGENESIS OF LEU-85, AND SITE.
RX PubMed=11335724; DOI=10.1074/jbc.m102428200;
RA Klein R.C., Prorok M., Galdzicki Z., Castellino F.J.;
RT "The amino acid residue at sequence position 5 in the conantokin peptides
RT partially governs subunit-selective antagonism of recombinant N-methyl-D-
RT aspartate receptors.";
RL J. Biol. Chem. 276:26860-26867(2001).
RN [5]
RP METAL-BINDING SITES, AND COFACTOR.
RX PubMed=10406223; DOI=10.1034/j.1399-3011.1999.00042.x;
RA Blandl T., Warder S.E., Prorok M., Castellino F.J.;
RT "Binding of cations to individual gamma-carboxyglutamate residues of
RT conantokin-G and conantokin-T.";
RL J. Pept. Res. 53:453-464(1999).
RN [6]
RP THERAPEUTIC USAGE.
RX PubMed=12507705; DOI=10.1016/s0304-3959(02)00303-2;
RA Malmberg A.B., Gilbert H., McCabe R.T., Basbaum A.I.;
RT "Powerful antinociceptive effects of the cone snail venom-derived subtype-
RT selective NMDA receptor antagonists conantokins G and T.";
RL Pain 101:109-116(2003).
RN [7]
RP STRUCTURE BY NMR OF 81-97.
RX PubMed=9188685; DOI=10.1021/bi970321w;
RA Rigby A.C., Baleja J.D., Furie B.C., Furie B.;
RT "Three-dimensional structure of a gamma-carboxyglutamic acid-containing
RT conotoxin, conantokin G, from the marine snail Conus geographus: the metal-
RT free conformer.";
RL Biochemistry 36:6906-6914(1997).
RN [8]
RP STRUCTURE BY NMR OF 81-97.
RX PubMed=9398296; DOI=10.1021/bi9718550;
RA Rigby A.C., Baleja J.D., Li L., Pedersen L.G., Furie B.C., Furie B.;
RT "Role of gamma-carboxyglutamic acid in the calcium-induced structural
RT transition of conantokin G, a conotoxin from the marine snail Conus
RT geographus.";
RL Biochemistry 36:15677-15684(1997).
RN [9]
RP STRUCTURE BY NMR OF 81-97.
RX PubMed=8999936; DOI=10.1074/jbc.272.4.2291;
RA Skjaerbaek N., Nielsen K.J., Lewis R.J., Alewood P.F., Craik D.J.;
RT "Determination of the solution structures of conantokin-G and conantokin-T
RT by CD and NMR spectroscopy.";
RL J. Biol. Chem. 272:2291-2299(1997).
RN [10]
RP STRUCTURE BY NMR OF WILD-TYPE AND MUTANT CON-G, MUTAGENESIS OF GLN-89, AND
RP COFACTOR.
RX PubMed=26048991; DOI=10.1074/jbc.m115.650341;
RA Kunda S., Yuan Y., Balsara R.D., Zajicek J., Castellino F.J.;
RT "Hydroxyproline-induced helical disruption in conantokin Rl-B affects
RT subunit-selective antagonistic activities toward ion channels of N-methyl-
RT D-aspartate receptors.";
RL J. Biol. Chem. 290:18156-18172(2015).
CC -!- FUNCTION: Conantokins inhibit N-methyl-D-aspartate (NMDA) receptors.
CC This toxin is selective for the NR2B/GRIN2B subunit. Induces sleep-like
CC symptoms in young mice and hyperactivity in older mice.
CC {ECO:0000269|PubMed:2165278}.
CC -!- COFACTOR:
CC Name=Ca(2+); Xref=ChEBI:CHEBI:29108;
CC Evidence={ECO:0000269|PubMed:10406223};
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:10406223, ECO:0000269|PubMed:26048991};
CC Note=Divalent cations stabilize the toxin the in alpha-helix
CC conformation. {ECO:0000269|PubMed:10406223,
CC ECO:0000269|PubMed:26048991};
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:6501296}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom duct.
CC {ECO:0000305|PubMed:6501296}.
CC -!- PHARMACEUTICAL: Failed in phase II clinical trial. Was tested under the
CC name CGX-1007 by Cognetix Inc. to treat convulsion and epilepsy.
CC -!- MISCELLANEOUS: The mutant Gln-89 consists of the addition of a proline
CC residue which is hydroxylated (4-hydroxyproline).
CC {ECO:0000269|PubMed:26048991}.
CC -!- MISCELLANEOUS: The mature peptide does not contain cysteine residue.
CC {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the conotoxin B superfamily. {ECO:0000305}.
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DR EMBL; AF043141; AAC15669.1; -; mRNA.
DR PIR; A05168; A05168.
DR PDB; 1AD7; NMR; -; A=81-97.
DR PDB; 1AWY; NMR; -; A=81-97.
DR PDB; 1ONU; NMR; -; A=81-97.
DR PDB; 2DPQ; X-ray; 1.25 A; A=81-97.
DR PDB; 2MZL; NMR; -; A=81-97.
DR PDB; 2MZM; NMR; -; A=81-97.
DR PDBsum; 1AD7; -.
DR PDBsum; 1AWY; -.
DR PDBsum; 1ONU; -.
DR PDBsum; 2DPQ; -.
DR PDBsum; 2MZL; -.
DR PDBsum; 2MZM; -.
DR AlphaFoldDB; P07231; -.
DR SMR; P07231; -.
DR TCDB; 8.B.35.1.1; the conantokin (conantokin) family.
DR ConoServer; 1373; Conantokin-G precursor.
DR ConoServer; 1353; Conantokin-G precursor (variant).
DR EvolutionaryTrace; P07231; -.
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:0099106; F:ion channel regulator activity; IEA:UniProtKB-KW.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
DR InterPro; IPR005918; Conantokin_CS.
DR PROSITE; PS60025; CONANTOKIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Amidation; Calcium; Cleavage on pair of basic residues;
KW Direct protein sequencing; Gamma-carboxyglutamic acid;
KW Ion channel impairing toxin; Ionotropic glutamate receptor inhibitor;
KW Magnesium; Metal-binding; Neurotoxin; Pharmaceutical;
KW Postsynaptic neurotoxin; Secreted; Signal; Toxin.
FT SIGNAL 1..21
FT /evidence="ECO:0000255"
FT PROPEP 22..80
FT /evidence="ECO:0000269|PubMed:6501296"
FT /id="PRO_0000035060"
FT PEPTIDE 81..97
FT /note="Conantokin-G"
FT /evidence="ECO:0000269|PubMed:6501296"
FT /id="PRO_0000035061"
FT REGION 52..100
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 61..80
FT /note="Gamma-carboxylation recognition sequence that plays
FT a role in the conversion of Glu to carboxy-Glu (Gla)"
FT /evidence="ECO:0000305"
FT COMPBIAS 56..100
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 83
FT /ligand="a divalent metal cation"
FT /ligand_id="ChEBI:CHEBI:60240"
FT /note="via 4-carboxyglutamate"
FT /evidence="ECO:0000269|PubMed:10406223,
FT ECO:0000269|PubMed:26048991, ECO:0000312|PDB:2DPQ"
FT BINDING 87
FT /ligand="a divalent metal cation"
FT /ligand_id="ChEBI:CHEBI:60240"
FT /note="via 4-carboxyglutamate"
FT /evidence="ECO:0000269|PubMed:10406223,
FT ECO:0000269|PubMed:26048991, ECO:0000312|PDB:2DPQ"
FT BINDING 90
FT /ligand="a divalent metal cation"
FT /ligand_id="ChEBI:CHEBI:60240"
FT /note="via 4-carboxyglutamate"
FT /evidence="ECO:0000269|PubMed:10406223,
FT ECO:0000269|PubMed:26048991, ECO:0000312|PDB:2DPQ"
FT BINDING 94
FT /ligand="a divalent metal cation"
FT /ligand_id="ChEBI:CHEBI:60240"
FT /note="via 4-carboxyglutamate"
FT /evidence="ECO:0000269|PubMed:10406223,
FT ECO:0000269|PubMed:26048991"
FT SITE 85
FT /note="Important for selectivity"
FT MOD_RES 83
FT /note="4-carboxyglutamate"
FT /evidence="ECO:0000269|PubMed:6501296"
FT MOD_RES 84
FT /note="4-carboxyglutamate"
FT /evidence="ECO:0000269|PubMed:6501296"
FT MOD_RES 87
FT /note="4-carboxyglutamate"
FT /evidence="ECO:0000269|PubMed:6501296"
FT MOD_RES 90
FT /note="4-carboxyglutamate"
FT /evidence="ECO:0000269|PubMed:6501296"
FT MOD_RES 94
FT /note="4-carboxyglutamate"
FT /evidence="ECO:0000269|PubMed:6501296"
FT MOD_RES 97
FT /note="Asparagine amide"
FT /evidence="ECO:0000269|PubMed:6501296"
FT VARIANT 85
FT /note="L -> V"
FT /evidence="ECO:0000269|PubMed:9488665"
FT MUTAGEN 85
FT /note="L->I: No loss of inhibition of NR1a/NR2B receptor;
FT no inhibition of NR1a/NR2A receptor (as for the wild-
FT type)."
FT /evidence="ECO:0000269|PubMed:11335724"
FT MUTAGEN 85
FT /note="L->V: No loss of inhibition of NR1a/NR2B receptor;
FT no inhibition of NR1a/NR2A receptor (as for the wild-
FT type)."
FT /evidence="ECO:0000269|PubMed:11335724"
FT MUTAGEN 85
FT /note="L->Y: Little loss of inhibition of NR1a/NR2B
FT receptor; 70% of inhibition of NR1a/NR2A receptor."
FT /evidence="ECO:0000269|PubMed:11335724"
FT MUTAGEN 89
FT /note="Q->QP: Loss of inhibition of NMDA receptors from
FT mouse cortical neurons (the Pro is hydroxylated)."
FT /evidence="ECO:0000269|PubMed:26048991,
FT ECO:0000312|PDB:2MZL"
FT HELIX 82..96
FT /evidence="ECO:0007829|PDB:2DPQ"
SQ SEQUENCE 100 AA; 11267 MW; 3B0050FDFF2B9DFB CRC64;
MHLYTYLYLL VPLVTFHLIL GTGTLDDGGA LTERRSADAT ALKAEPVLLQ KSAARSTDDN
GKDRLTQMKR ILKQRGNKAR GEEELQENQE LIREKSNGKR
