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}.
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; 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
FT                   wild-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
FT                   wild-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
//