CKR1B_CONRO
ID CKR1B_CONRO Reviewed; 96 AA.
AC P0DKZ0;
DT 03-APR-2013, integrated into UniProtKB/Swiss-Prot.
DT 03-APR-2013, sequence version 1.
DT 03-AUG-2022, entry version 29.
DE RecName: Full=Conantokin Rl-B {ECO:0000305};
DE Short=Con Rl-B {ECO:0000303|PubMed:27981829};
DE Short=ConRl-B {ECO:0000303|PubMed:22594498, ECO:0000303|PubMed:27981829};
DE Flags: Precursor; Fragment;
OS Conus rolani (Cone snail).
OC Eukaryota; Metazoa; Spiralia; Lophotrochozoa; Mollusca; Gastropoda;
OC Caenogastropoda; Neogastropoda; Conoidea; Conidae; Conus; Asprella.
OX NCBI_TaxID=745791;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], SYNTHESIS OF 79-96, FUNCTION, BIOASSAY,
RP MUTAGENESIS OF LEU-83; GLU-85 AND GLU-93, SITES, CIRCULAR DICHROISM
RP ANALYSIS, GAMMA-CARBOXYGLUTAMATION AT GLU-81; GLU-82; GLU-85; GLU-89 AND
RP GLU-93, HYDROXYLATION AT PRO-88, AMIDATION AT ASN-96, AND COFACTOR.
RX PubMed=22594498; DOI=10.1021/bi300055n;
RA Gowd K.H., Han T.S., Twede V., Gajewiak J., Smith M.D., Watkins M.,
RA Platt R.J., Toledo G., White H.S., Olivera B.M., Bulaj G.;
RT "Conantokins derived from the Asprella clade impart conRl-B, an N-methyl d-
RT aspartate receptor antagonist with a unique selectivity profile for NR2B
RT subunits.";
RL Biochemistry 51:4685-4692(2012).
RN [2]
RP STRUCTURE BY NMR OF WILD-TYPE AND MUTANT, METAL-BINDING SITES, FUNCTION,
RP MUTAGENESIS OF 86-LYS--PRO-89, AND 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).
RN [3]
RP STRUCTURE BY NMR OF MUTANTS PRO-88, MUTAGENESIS OF PRO-88, FUNCTION, AND
RP FUNCTION OF MUTANTS PRO-88.
RX PubMed=27981829; DOI=10.1021/acs.biochem.6b00962;
RA Yuan Y., Balsara R.D., Zajicek J., Kunda S., Castellino F.J.;
RT "Discerning the role of the hydroxyproline residue in the structure of
RT conantokin Rl-B and its role in GluN2B subunit-selective antagonistic
RT activity toward N-methyl-D-aspartate receptors.";
RL Biochemistry 55:7112-7122(2016).
CC -!- FUNCTION: Conantokins inhibit N-methyl-D-aspartate (NMDA) receptors.
CC This toxin has antagonist activity on the NR2B/GRIN2B subunit
CC (IC(50)=0.1 uM) (PubMed:22594498, PubMed:26048991, PubMed:27981829). In
CC vivo, when delivered into the brain, is active has anticonvulsant
CC activity in the model of epilepsy in mice (PubMed:22594498).
CC {ECO:0000269|PubMed:22594498, ECO:0000269|PubMed:26048991,
CC ECO:0000269|PubMed:27981829}.
CC -!- COFACTOR:
CC Name=Ca(2+); Xref=ChEBI:CHEBI:29108;
CC Evidence={ECO:0000269|PubMed:22594498};
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:26048991};
CC Note=Divalent cations stabilize the toxin the in alpha-helix
CC conformation. {ECO:0000269|PubMed:22594498,
CC ECO:0000269|PubMed:26048991};
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000305}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom duct. {ECO:0000305}.
CC -!- PTM: Hydroxylation of Pro-88 is important for NR2B/GRIN2B NMDA receptor
CC selectivity (PubMed:26048991, PubMed:27981829). Removal of
CC hydroxylation does not change global NMDA receptor antagonism (tested
CC on WT neurons), but it decreases the inhibitory potency on NR2B/GRIN2B
CC NMDA receptors and increases the inhibitory potency on NR2A/GRIN2A NMDA
CC receptors. Hydroxylation of Pro-88 locally disrupts a small region of
CC the divalent cation-induced alpha-helix but does not destabilize the
CC entire helix (PubMed:26048991, PubMed:27981829).
CC {ECO:0000269|PubMed:26048991, ECO:0000269|PubMed:27981829}.
CC -!- MISCELLANEOUS: The mature peptide does not contain cysteine residue.
CC {ECO:0000305}.
CC -!- MISCELLANEOUS: Has no or very weak antagonist activity on NR2A/GRIN2A,
CC NR2C/GRIN2C, and NR2D/GRIN2D subunits. {ECO:0000269|PubMed:22594498}.
CC -!- SIMILARITY: Belongs to the conotoxin B superfamily. {ECO:0000305}.
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DR PDB; 2MYZ; NMR; -; A=79-96.
DR PDB; 2MZK; NMR; -; A=79-96.
DR PDB; 5TBG; NMR; -; A=79-96.
DR PDB; 5TBQ; NMR; -; A=79-96.
DR PDB; 5TBR; NMR; -; A=79-96.
DR PDBsum; 2MYZ; -.
DR PDBsum; 2MZK; -.
DR PDBsum; 5TBG; -.
DR PDBsum; 5TBQ; -.
DR PDBsum; 5TBR; -.
DR AlphaFoldDB; P0DKZ0; -.
DR BMRB; P0DKZ0; -.
DR SMR; P0DKZ0; -.
DR ConoServer; 5849; Conantokin-Rl2 precursor.
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 3: Inferred from homology;
KW 3D-structure; Amidation; Calcium; Gamma-carboxyglutamic acid;
KW Hydroxylation; Ion channel impairing toxin;
KW Ionotropic glutamate receptor inhibitor; Magnesium; Metal-binding;
KW Neurotoxin; Postsynaptic neurotoxin; Secreted; Signal; Toxin.
FT SIGNAL 1..21
FT /evidence="ECO:0000255"
FT PROPEP 22..78
FT /evidence="ECO:0000305|PubMed:22594498"
FT /id="PRO_0000421894"
FT PEPTIDE 79..96
FT /note="Conantokin Rl-B"
FT /evidence="ECO:0000305|PubMed:22594498"
FT /id="PRO_0000421895"
FT REGION 51..96
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 61..96
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 81
FT /ligand="a divalent metal cation"
FT /ligand_id="ChEBI:CHEBI:60240"
FT /note="via 4-carboxyglutamate"
FT /evidence="ECO:0000269|PubMed:26048991"
FT BINDING 85
FT /ligand="a divalent metal cation"
FT /ligand_id="ChEBI:CHEBI:60240"
FT /note="via 4-carboxyglutamate"
FT /evidence="ECO:0000269|PubMed:26048991"
FT BINDING 89
FT /ligand="a divalent metal cation"
FT /ligand_id="ChEBI:CHEBI:60240"
FT /note="via 4-carboxyglutamate"
FT /evidence="ECO:0000269|PubMed:26048991"
FT BINDING 93
FT /ligand="a divalent metal cation"
FT /ligand_id="ChEBI:CHEBI:60240"
FT /note="via 4-carboxyglutamate"
FT /evidence="ECO:0000269|PubMed:26048991"
FT SITE 86
FT /note="Important for selectivity"
FT /evidence="ECO:0000305|PubMed:22594498,
FT ECO:0000305|PubMed:26048991, ECO:0000305|PubMed:27981829"
FT SITE 88
FT /note="Important for activity (Pro and hydroxyPro)"
FT /evidence="ECO:0000305|PubMed:22594498,
FT ECO:0000305|PubMed:26048991, ECO:0000305|PubMed:27981829"
FT MOD_RES 81
FT /note="4-carboxyglutamate"
FT /evidence="ECO:0000250|UniProtKB:P07231,
FT ECO:0000305|PubMed:22594498"
FT MOD_RES 82
FT /note="4-carboxyglutamate"
FT /evidence="ECO:0000250|UniProtKB:P07231,
FT ECO:0000305|PubMed:22594498"
FT MOD_RES 85
FT /note="4-carboxyglutamate"
FT /evidence="ECO:0000250|UniProtKB:P07231,
FT ECO:0000305|PubMed:22594498"
FT MOD_RES 88
FT /note="4-hydroxyproline"
FT /evidence="ECO:0000305|PubMed:22594498"
FT MOD_RES 89
FT /note="4-carboxyglutamate"
FT /evidence="ECO:0000250|UniProtKB:P07231,
FT ECO:0000305|PubMed:22594498"
FT MOD_RES 93
FT /note="4-carboxyglutamate"
FT /evidence="ECO:0000250|UniProtKB:P07231,
FT ECO:0000305|PubMed:22594498"
FT MOD_RES 96
FT /note="Asparagine amide"
FT /evidence="ECO:0000250|UniProtKB:P07231,
FT ECO:0000305|PubMed:22594498"
FT MUTAGEN 83
FT /note="L->Y: No change in activity."
FT /evidence="ECO:0000269|PubMed:22594498"
FT MUTAGEN 85
FT /note="E->K: No change in activity."
FT /evidence="ECO:0000269|PubMed:22594498"
FT MUTAGEN 86..88
FT /note="KAP->NQ: Loss of inhibition of NMDA receptors from
FT mouse cortical neurons."
FT /evidence="ECO:0000269|PubMed:26048991,
FT ECO:0000312|PDB:2MYZ"
FT MUTAGEN 88
FT /note="P->A: Decrease in inhibitory potency on NMDA
FT receptors, but no loss in NR2B/GRIN2B NMDA receptor
FT selectivity."
FT /evidence="ECO:0000269|PubMed:27981829,
FT ECO:0000312|PDB:5TBR"
FT MUTAGEN 88
FT /note="Missing: Decrease in inhibitory potency on NMDA
FT receptors."
FT /evidence="ECO:0000269|PubMed:27981829,
FT ECO:0000312|PDB:5TBQ"
FT MUTAGEN 93
FT /note="E->K: No change in activity."
FT /evidence="ECO:0000269|PubMed:22594498"
FT NON_TER 96
FT HELIX 80..84
FT /evidence="ECO:0007829|PDB:2MYZ"
FT HELIX 86..93
FT /evidence="ECO:0007829|PDB:2MYZ"
FT TURN 94..96
FT /evidence="ECO:0007829|PDB:5TBQ"
SQ SEQUENCE 96 AA; 10756 MW; 47A95FF6CCCC6813 CRC64;
MQLYTYLYLL VPLVTFHLIL GTGTLDHGDA LTERRSTDAT ALKPEPVLLQ KSSARSTNDN
GKDTQMKRIL KKRGNKARGE EELAEKAPEF ARELAN
