CKT_CONTU
ID CKT_CONTU Reviewed; 21 AA.
AC P17684;
DT 01-AUG-1990, integrated into UniProtKB/Swiss-Prot.
DT 01-AUG-1990, sequence version 1.
DT 03-AUG-2022, entry version 97.
DE RecName: Full=Conantokin-T {ECO:0000303|PubMed:2180939};
DE Short=Con-T {ECO:0000303|PubMed:2180939};
OS Conus tulipa (Fish-hunting cone snail) (Tulip cone).
OC Eukaryota; Metazoa; Spiralia; Lophotrochozoa; Mollusca; Gastropoda;
OC Caenogastropoda; Neogastropoda; Conoidea; Conidae; Conus; Gastridium.
OX NCBI_TaxID=6495;
RN [1]
RP PROTEIN SEQUENCE, AMIDATION AT ALA-21, GAMMA-CARBOXYGLUTAMATION AT GLU-3;
RP GLU-4; GLU-10 AND GLU-14, AND SUBCELLULAR LOCATION.
RC TISSUE=Venom;
RX PubMed=2180939; DOI=10.1016/s0021-9258(19)39285-3;
RA Haack J.A., Rivier J.E., Parks T.N., Mena E.E., Cruz L.J., Olivera B.M.;
RT "Conantokin-T. A gamma-carboxyglutamate containing peptide with N-methyl-D-
RT aspartate antagonist activity.";
RL J. Biol. Chem. 265:6025-6029(1990).
RN [2]
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 [3]
RP METAL-BINDING SITES.
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 [4]
RP MUTAGENESIS OF TYR-5, 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 PHARMACEUTICAL.
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 [6]
RP STRUCTURE BY NMR.
RX PubMed=9247135; DOI=10.1016/s0014-5793(97)00573-5;
RA Warder S.E., Chen Z., Zhu Y., Prorok M., Castellino F.J., Ni F.;
RT "The NMR solution structure of the NMDA receptor antagonist, conantokin-T,
RT in the absence of divalent metal ions.";
RL FEBS Lett. 411:19-26(1997).
RN [7]
RP STRUCTURE BY NMR.
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).
CC -!- FUNCTION: Conantokins inhibit N-methyl-D-aspartate (NMDA) receptors.
CC This toxin inhibits both NR2A/GRIN2A and NR2B/GRIN2B subunits of N-
CC methyl-D-aspartate (NMDA) receptor-mediated calcium influx in central
CC nervous system neurons. Induces sleep-like symptoms in young mice and
CC hyperactivity in older mice. {ECO:0000269|PubMed:2165278}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:2180939}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom duct. {ECO:0000305}.
CC -!- PHARMACEUTICAL: Failed in phase II clinical trial. Was tested by
CC Cognetix Inc. to treat antinociceptive effects in several models of
CC injury-induced pain.
CC -!- MISCELLANEOUS: Adopts an alpha-helical conformation in presence and in
CC absence of divalent cations. {ECO:0000269|PubMed:9247135}.
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 PIR; A35225; A35225.
DR PDB; 1ONT; NMR; -; A=1-21.
DR PDB; 2DPR; X-ray; 1.70 A; A/B=1-21.
DR PDBsum; 1ONT; -.
DR PDBsum; 2DPR; -.
DR AlphaFoldDB; P17684; -.
DR SMR; P17684; -.
DR ConoServer; 1269; Conantokin-T.
DR EvolutionaryTrace; P17684; -.
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 Pfam; PF10550; Toxin_36; 1.
DR PROSITE; PS60025; CONANTOKIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Amidation; Calcium; Direct protein sequencing;
KW Gamma-carboxyglutamic acid; Ion channel impairing toxin;
KW Ionotropic glutamate receptor inhibitor; Magnesium; Metal-binding;
KW Neurotoxin; Pharmaceutical; Postsynaptic neurotoxin; Secreted; Toxin.
FT PEPTIDE 1..21
FT /note="Conantokin-T"
FT /evidence="ECO:0000269|PubMed:2180939"
FT /id="PRO_0000044504"
FT BINDING 10
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:0000312|PDB:2DPR"
FT BINDING 14
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:0000312|PDB:2DPR"
FT SITE 5
FT /note="Important for selectivity"
FT /evidence="ECO:0000305|PubMed:11335724"
FT MOD_RES 3
FT /note="4-carboxyglutamate"
FT /evidence="ECO:0000269|PubMed:2180939"
FT MOD_RES 4
FT /note="4-carboxyglutamate"
FT /evidence="ECO:0000269|PubMed:2180939"
FT MOD_RES 10
FT /note="4-carboxyglutamate"
FT /evidence="ECO:0000269|PubMed:2180939"
FT MOD_RES 14
FT /note="4-carboxyglutamate"
FT /evidence="ECO:0000269|PubMed:2180939"
FT MOD_RES 21
FT /note="Alanine amide"
FT /evidence="ECO:0000269|PubMed:2180939"
FT MUTAGEN 5
FT /note="Y->F: No loss of inhibition of NR1a/NR2B receptor;
FT little loss of inhibition of NR1a/NR2A receptor."
FT /evidence="ECO:0000269|PubMed:11335724"
FT MUTAGEN 5
FT /note="Y->V: Little loss of inhibition of NR1a/NR2B
FT receptor; important loss of inhibition of NR1a/NR2A
FT receptor."
FT /evidence="ECO:0000269|PubMed:11335724"
FT MUTAGEN 5
FT /note="Y->W: Little loss of inhibition of NR1a/NR2B
FT receptor; complete loss of inhibition of NR1a/NR2A
FT receptor."
FT /evidence="ECO:0000269|PubMed:11335724"
FT HELIX 3..20
FT /evidence="ECO:0007829|PDB:2DPR"
SQ SEQUENCE 21 AA; 2509 MW; 7F7B893AC4842C38 CRC64;
GEEEYQKMLE NLREAEVKKN A
