CM3A_CONKI
ID CM3A_CONKI Reviewed; 22 AA.
AC P0C195;
DT 18-APR-2006, integrated into UniProtKB/Swiss-Prot.
DT 22-NOV-2017, sequence version 2.
DT 03-AUG-2022, entry version 54.
DE RecName: Full=Mu-conotoxin KIIIB {ECO:0000303|PubMed:23167564};
DE Contains:
DE RecName: Full=Mu-conotoxin KIIIA {ECO:0000303|PubMed:15882064};
DE Flags: Precursor; Fragment;
OS Conus kinoshitai (Kinoshita's cone).
OC Eukaryota; Metazoa; Spiralia; Lophotrochozoa; Mollusca; Gastropoda;
OC Caenogastropoda; Neogastropoda; Conoidea; Conidae; Conus; Afonsoconus.
OX NCBI_TaxID=376876;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 5-22, FUNCTION, SYNTHESIS OF 5-20, AND
RP AMIDATION AT CYS-20.
RC TISSUE=Venom duct;
RX PubMed=15882064; DOI=10.1021/bi0473408;
RA Bulaj G., West P.J., Garrett J.E., Watkins M., Zhang M.-M., Norton R.S.,
RA Smith B.J., Yoshikami D., Olivera B.M.;
RT "Novel conotoxins from Conus striatus and Conus kinoshitai selectively
RT block TTX-resistant sodium channels.";
RL Biochemistry 44:7259-7265(2005).
RN [2]
RP ERRATUM OF PUBMED:15882064.
RX DOI=10.1021/bi068001c;
RA Bulaj G., West P.J., Garrett J.E., Watkins M., Zhang M.-M., Norton R.S.,
RA Smith B.J., Yoshikami D., Olivera B.M.;
RL Biochemistry 45:3116-3116(2006).
RN [3]
RP FUNCTION, SYNTHESIS OF 5-20, AND MUTAGENESIS OF LYS-11; TRP-12; ARG-14;
RP ASP-15; HIS-16 AND ARG-18.
RX PubMed=17724025; DOI=10.1074/jbc.m704616200;
RA Zhang M.-M., Green B.R., Catlin P., Fiedler B., Azam L., Chadwick A.,
RA Terlau H., McArthur J.R., French R.J., Gulyas J., Rivier J.E., Smith B.J.,
RA Norton R.S., Olivera B.M., Yoshikami D., Bulaj G.;
RT "Structure/function characterization of mu-conotoxin KIIIA, an analgesic,
RT nearly irreversible blocker of mammalian neuronal sodium channels.";
RL J. Biol. Chem. 282:30699-30706(2007).
RN [4]
RP FUNCTION, AND SYNTHESIS OF 5-20.
RX PubMed=18950653; DOI=10.1016/j.toxicon.2008.10.017;
RA Holford M., Zhang M.-M., Gowd K.H., Azam L., Green B.R., Watkins M.,
RA Ownby J.-P., Yoshikami D., Bulaj G., Olivera B.M.;
RT "Pruning nature: biodiversity-derived discovery of novel sodium channel
RT blocking conotoxins from Conus bullatus.";
RL Toxicon 53:90-98(2009).
RN [5]
RP FUNCTION, AND MUTAGENESIS OF LYS-11.
RX PubMed=19221510; DOI=10.4161/chan.3.1.7500;
RA Zhang M.M., McArthur J.R., Azam L., Bulaj G., Olivera B.M., French R.J.,
RA Yoshikami D.;
RT "Synergistic and antagonistic interactions between tetrodotoxin and mu-
RT conotoxin in blocking voltage-gated sodium channels.";
RL Channels 3:32-38(2009).
RN [6]
RP FUNCTION, SYNTHESIS OF 5-20, AND MUTAGENESIS OF TRP-12.
RX PubMed=21781281; DOI=10.1111/j.1742-4658.2011.08264.x;
RA Van Der Haegen A., Peigneur S., Tytgat J.;
RT "Importance of position 8 in mu-conotoxin KIIIA for voltage-gated sodium
RT channel selectivity.";
RL FEBS J. 278:3408-3418(2011).
RN [7]
RP FUNCTION, SYNTHESIS OF 5-20, AND MUTAGENESIS OF LYS-11; ARG-14; HIS-16 AND
RP ARG-18.
RX PubMed=21709136; DOI=10.1124/mol.111.073460;
RA McArthur J.R., Singh G., McMaster D., Winkfein R., Tieleman D.P.,
RA French R.J.;
RT "Interactions of key charged residues contributing to selective block of
RT neuronal sodium channels by mu-conotoxin KIIIA.";
RL Mol. Pharmacol. 80:573-584(2011).
RN [8]
RP FUNCTION, AND SYNTHESIS OF 5-20.
RX PubMed=21652775; DOI=10.1073/pnas.1107027108;
RA Wilson M.J., Yoshikami D., Azam L., Gajewiak J., Olivera B.M., Bulaj G.,
RA Zhang M.M.;
RT "mu-Conotoxins that differentially block sodium channels Nav1.1 through 1.8
RT identify those responsible for action potentials in sciatic nerve.";
RL Proc. Natl. Acad. Sci. U.S.A. 108:10302-10307(2011).
RN [9]
RP FUNCTION.
RX PubMed=23146020; DOI=10.1111/bph.12051;
RA Zhang M.M., Wilson M.J., Azam L., Gajewiak J., Rivier J.E., Bulaj G.,
RA Olivera B.M., Yoshikami D.;
RT "Co-expression of Na(V)beta subunits alters the kinetics of inhibition of
RT voltage-gated sodium channels by pore-blocking mu-conotoxins.";
RL Br. J. Pharmacol. 168:1597-1610(2013).
RN [10]
RP FUNCTION.
RX PubMed=25658507; DOI=10.1021/jm501765v;
RA Murray J.K., Ligutti J., Liu D., Zou A., Poppe L., Li H., Andrews K.L.,
RA Moyer B.D., McDonough S.I., Favreau P., Stoecklin R., Miranda L.P.;
RT "Engineering potent and selective analogues of GpTx-1, a tarantula venom
RT peptide antagonist of the Na(V)1.7 sodium channel.";
RL J. Med. Chem. 58:2299-2314(2015).
RN [11]
RP STRUCTURE BY NMR OF 5-20 (MU-CONOTOXIN KIIIA), SYNTHESIS OF 5-20, SUBUNIT,
RP AND MUTAGENESIS OF CYS-5 AND CYS-13.
RX PubMed=19170536; DOI=10.1021/bi801998a;
RA Khoo K.K., Feng Z.-P., Smith B.J., Zhang M.-M., Yoshikami D., Olivera B.M.,
RA Bulaj G., Norton R.S.;
RT "Structure of the analgesic mu-conotoxin KIIIA and effects on the structure
RT and function of disulfide deletion.";
RL Biochemistry 48:1210-1219(2009).
RN [12]
RP STRUCTURE BY NMR OF 3-20 AND 5-20 (MU-CONOTOXIN KIIIA AND KIIIB), SYNTHESIS
RP OF 3-20 AND 5-20, FUNCTION, AND DISULFIDE BOND OF SYNTHETIC PEPTIDES (P1
RP AND P2).
RX PubMed=23167564; DOI=10.1021/bi301256s;
RA Khoo K.K., Gupta K., Green B.R., Zhang M.M., Watkins M., Olivera B.M.,
RA Balaram P., Yoshikami D., Bulaj G., Norton R.S.;
RT "Distinct disulfide isomers of mu-conotoxins KIIIA and KIIIB block voltage-
RT gated sodium channels.";
RL Biochemistry 51:9826-9835(2012).
RN [13]
RP STRUCTURE BY ELECTRON MICROSCOPY (3.0 ANGSTROMS) OF 5-20 (MU-CONOTOXIN
RP KIIIA) IN COMPLEX WITH SUBUNITS ALPHA AND BETA-2 OF NAV1.2, AND DISULFIDE
RP BOND.
RX PubMed=30765605; DOI=10.1126/science.aaw2999;
RA Pan X., Li Z., Huang X., Huang G., Gao S., Shen H., Liu L., Lei J., Yan N.;
RT "Molecular basis for pore blockade of human Na+ channel Nav1.2 by the mu-
RT conotoxin KIIIA.";
RL Science 363:1309-1313(2019).
RN [14]
RP STRUCTURE BY NMR OF 5-20, FUNCTION, SYNTHESIS OF 5-20, DISULFIDE BOND OF
RP SYNTHETIC PEPTIDES (P1; P2 AND N), AND 3D-STRUCTURE MODELING IN COMPLEX
RP WITH SODIUM CHANNEL NAV12/SCN2A.
RX PubMed=35167877; DOI=10.1016/j.jbc.2022.101728;
RA Tran H.N.T., McMahon K.L., Deuis J.R., Vetter I., Schroeder C.I.;
RT "Structural and functional insights into the inhibition of human voltage-
RT gated sodium channels by mu-conotoxin KIIIA disulfide isomers.";
RL J. Biol. Chem. 298:101728-101728(2022).
CC -!- FUNCTION: Mu-conotoxin KIIIA-P1: mu-conotoxins block voltage-gated
CC sodium channels (Nav). This toxin potently blocks Nav1.2/SCN2A
CC (IC(50)5-124 nM), Nav1.4/SCN4A (IC(50)=20-90 nM), and Nav1.7/SCN9A
CC (IC(50)=290-413 nM) (PubMed:17724025, PubMed:19221510, PubMed:21781281,
CC PubMed:21709136,PubMed:21652775, PubMed:23146020, PubMed:25658507,
CC PubMed:35167877). It moderately blocks Nav1.1/SCN1A, and mNav1.6/SCN8A
CC (PubMed:17724025, PubMed:21781281, PubMed:21709136, PubMed:21652775,
CC PubMed:23146020, PubMed:25658507, PubMed:35167877). It also shows a
CC very low activity on Nav1.3/SCN3A (PubMed:17724025, PubMed:21781281).
CC This toxin binds a microsite within the pore different from the
CC tetrodotoxin binding site 1 (tested on Nav1.2) (PubMed:19221510). The
CC block is partial, with a residual current that can be completely
CC blocked by TTX (PubMed:19221510). The toxin probably docks at a more
CC superficial site in the outer vestibule of the channel than does TTX
CC (PubMed:19221510). On rNav1.2/SCN2A, it produces a block that is only
CC partially reversible. The block of Nav1.7 is modified when beta-
CC subunits are coexpressed with the alpha subunit (PubMed:23146020).
CC Hence, blocks of channels containing beta-1 and beta-3 subunits are
CC more potent (compared to channels without beta subunits), whereas
CC blocks of channels containing beta-2 and beta-4 subunits are less
CC potent (compared to channels without beta subunits) (PubMed:23146020).
CC {ECO:0000269|PubMed:15882064, ECO:0000269|PubMed:17724025,
CC ECO:0000269|PubMed:18950653, ECO:0000269|PubMed:19221510,
CC ECO:0000269|PubMed:21652775, ECO:0000269|PubMed:21709136,
CC ECO:0000269|PubMed:21781281, ECO:0000269|PubMed:23146020,
CC ECO:0000269|PubMed:25658507}.
CC -!- FUNCTION: Mu-conotoxin KIIIA-P2: This toxin potently blocks
CC Nav1.2/SCN2A (Kd=230 nM, IC(50)=1.37 uM) and Nav1.4/SCN4A (Kd=830 nM,
CC IC(50)=2 uM). It also moderately blocks Nav1.7/SCN9A (Kd=1.57 uM,
CC IC(50)=5.4 uM) (PubMed:35167877, PubMed:23167564). In addition, this
CC toxin may also inhibit other sodium channels, as does Mu-conotoxin
CC KIIIA-P1 (PubMed:23167564). {ECO:0000269|PubMed:23167564,
CC ECO:0000269|PubMed:35167877}.
CC -!- FUNCTION: Mu-conotoxin KIIIA-N: This toxin moderately blocks
CC Nav1.2/SCN2A (IC(50)=875 nM), Nav1.4/SCN4A (IC(50)=472 nM), and
CC Nav1.7/SCN9A (IC(50)=887 nM) (PubMed:35167877).
CC {ECO:0000269|PubMed:35167877}.
CC -!- FUNCTION: Mu-conotoxin KIIIB-P1: This toxin potently blocks
CC Nav1.2/SCN2A (Kd=470 nM). In addition, this toxin may also inhibit
CC other sodium channels, as does Mu-conotoxin KIIIA-P1.
CC {ECO:0000269|PubMed:23167564}.
CC -!- FUNCTION: Mu-conotoxin KIIIB-P2: This toxin potently blocks
CC Nav1.2/SCN2A (Kd=26 nM). In addition, this toxin may also inhibit other
CC sodium channels, as does Mu-conotoxin KIIIA-P1.
CC {ECO:0000269|PubMed:23167564}.
CC -!- SUBUNIT: Monomer. {ECO:0000269|PubMed:19170536}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000305|PubMed:15882064}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom duct.
CC {ECO:0000305|PubMed:15882064}.
CC -!- DOMAIN: The cysteine framework is III (CC-C-C-CC). Classified in the M-
CC 5 branch, since 5 residues stand between the fourth and the fifth
CC cysteine residues. {ECO:0000305}.
CC -!- PTM: Toxins with three different disulfide connectivities have been
CC synthesized (PubMed:35167877, PubMed:23167564). The conotoxin mu-KIIIA-
CC P1 shows the connectivity C1-C5, C2-C4, and C3-C6, whereas mu-KIIIA-P2
CC shows the connectivity C1-C6, C2-C4, and C3-C5 (PubMed:23167564). The
CC conotoxin mu-KIIIA-N has the 'native' fold of the mu-conotoxin family
CC (C1-C4, C2-C5, and C3-C6) (PubMed:35167877). Mu-KIIIA-P1 and mu-KIIIA-
CC P2 are obtained by both thermodynamic oxidative folding and
CC regioselective synthesis (PubMed:35167877, PubMed:23167564). Mu-KIIIA-
CC P1 is the major oxidative folding product (PubMed:23167564). Mu-KIIIA-N
CC is only obtained by regioselective synthesis (PubMed:35167877).
CC {ECO:0000269|PubMed:23167564, ECO:0000269|PubMed:35167877}.
CC -!- MISCELLANEOUS: Has no effect on hNav1.5/SCN5A (PubMed:17724025,
CC PubMed:21781281, PubMed:25658507). Has no effect on hNav1.8/SCN10A
CC (PubMed:21781281). {ECO:0000269|PubMed:21781281,
CC ECO:0000269|PubMed:25658507}.
CC -!- SIMILARITY: Belongs to the conotoxin M superfamily. {ECO:0000305}.
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DR PDB; 2LXG; NMR; -; A=5-20.
DR PDB; 6J8E; EM; 3.00 A; D=5-20.
DR PDBsum; 2LXG; -.
DR PDBsum; 6J8E; -.
DR AlphaFoldDB; P0C195; -.
DR BMRB; P0C195; -.
DR SMR; P0C195; -.
DR TCDB; 8.B.28.1.4; the mu-conotoxin (mu-conotoxin) family.
DR ConoServer; 1694; KIIIA precursor.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0017080; F:sodium channel regulator activity; IEA:UniProtKB-KW.
DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
PE 2: Evidence at transcript level;
KW 3D-structure; Amidation; Cleavage on pair of basic residues;
KW Disulfide bond; Ion channel impairing toxin; Neurotoxin; Secreted; Toxin;
KW Voltage-gated sodium channel impairing toxin.
FT PROPEP <1..2
FT /evidence="ECO:0000305|PubMed:23167564"
FT /id="PRO_0000442339"
FT PEPTIDE 3..20
FT /note="Mu-conotoxin KIIIB"
FT /evidence="ECO:0000305|PubMed:23167564"
FT /id="PRO_0000442340"
FT PEPTIDE 5..20
FT /note="Mu-conotoxin KIIIA"
FT /evidence="ECO:0000305|PubMed:15882064"
FT /id="PRO_0000232662"
FT REGION 14..16
FT /note="Pharmacophore key residues"
FT /evidence="ECO:0000305|PubMed:17724025,
FT ECO:0000305|PubMed:30765605"
FT REGION 18..19
FT /note="Pharmacophore key residues"
FT /evidence="ECO:0000305|PubMed:17724025,
FT ECO:0000305|PubMed:30765605"
FT SITE 7
FT /note="Pharmacophore key residue"
FT /evidence="ECO:0000305|PubMed:30765605"
FT SITE 11
FT /note="Pharmacophore key residue, the side chain functions
FT like a cork in the bottleneck, with the positively charged
FT amine group preventing the penetration of sodium"
FT /evidence="ECO:0000305|PubMed:30765605"
FT SITE 12
FT /note="Pharmacophore key residue"
FT /evidence="ECO:0000305|PubMed:30765605"
FT MOD_RES 20
FT /note="Cysteine amide"
FT /evidence="ECO:0000305|PubMed:15882064"
FT DISULFID 5..20
FT /note="in KIIIA-P2 and KIIIB-P1; alternate"
FT /evidence="ECO:0000305|PubMed:23167564"
FT DISULFID 5..19
FT /note="in KIIIA-P1 and KIIIB-P2; alternate"
FT /evidence="ECO:0000305|PubMed:23167564,
FT ECO:0000305|PubMed:30765605, ECO:0007744|PDB:2LXG,
FT ECO:0007744|PDB:6J8E"
FT DISULFID 5..13
FT /note="in KIIIA-M; alternate"
FT /evidence="ECO:0000305|PubMed:35167877"
FT DISULFID 6..19
FT /note="in KIIIA-M; alternate"
FT /evidence="ECO:0000305|PubMed:35167877"
FT DISULFID 6..13
FT /note="in KIIIA-P1, KIIIA-P2, KIIIB-P1 and KIIIB-P2;
FT alternate"
FT /evidence="ECO:0000305|PubMed:23167564,
FT ECO:0000305|PubMed:30765605, ECO:0007744|PDB:2LXG,
FT ECO:0007744|PDB:6J8E"
FT DISULFID 8..20
FT /note="in KIIIA-P1, KIIIB-P2 and KIIIA-M; alternate"
FT /evidence="ECO:0000305|PubMed:23167564,
FT ECO:0000305|PubMed:30765605, ECO:0007744|PDB:2LXG,
FT ECO:0007744|PDB:6J8E"
FT DISULFID 8..19
FT /note="in KIIIA-P2 and KIIIB-P1; alternate"
FT /evidence="ECO:0000305|PubMed:23167564"
FT MUTAGEN 5
FT /note="C->A: Structure similar to wild-type toxin, even
FT with this disulfide bond deletion."
FT /evidence="ECO:0000269|PubMed:19170536"
FT MUTAGEN 11
FT /note="K->A: Decrease in ability to block Nav1.3, Nav1.4,
FT Nav1.6 and Nav1.7, but not Nav1.2. 21-fold decrease in
FT binding affinity for Nav1.2."
FT /evidence="ECO:0000269|PubMed:17724025,
FT ECO:0000269|PubMed:19221510, ECO:0000269|PubMed:21709136"
FT MUTAGEN 12
FT /note="W->A: Decrease in ability to block both Nav1.2 and
FT Nav1.4. Decrease in binding affinity for Nav1.2, Nav1.4,
FT and Nav1.7."
FT /evidence="ECO:0000269|PubMed:17724025,
FT ECO:0000269|PubMed:21781281"
FT MUTAGEN 12
FT /note="W->E: 200-fold decrease in ability to block Nav1.4.
FT Block of Nav1.2 is completely reversible."
FT /evidence="ECO:0000269|PubMed:17724025,
FT ECO:0000269|PubMed:21781281"
FT MUTAGEN 12
FT /note="W->Q: 70-fold decrease in ability to block Nav1.4.
FT Block of Nav1.2 is completely reversible."
FT /evidence="ECO:0000269|PubMed:17724025,
FT ECO:0000269|PubMed:21781281"
FT MUTAGEN 12
FT /note="W->R: 40-fold decrease in ability to block Nav1.4.
FT Block of Nav1.2 is completely reversible."
FT /evidence="ECO:0000269|PubMed:17724025,
FT ECO:0000269|PubMed:21781281"
FT MUTAGEN 13
FT /note="C->A: Structure similar to wild-type toxin, even
FT with this disulfide bond deletion."
FT /evidence="ECO:0000269|PubMed:19170536"
FT MUTAGEN 14
FT /note="R->A: Decrease in ability to block both Nav1.4 and
FT Nav1.2, and decrease in binding affinity for Nav1.2,
FT Nav1.4, and Nav1.7."
FT /evidence="ECO:0000269|PubMed:17724025,
FT ECO:0000269|PubMed:21709136"
FT MUTAGEN 15
FT /note="D->A: Decrease in ability to inhibit both Nav1.4 and
FT Nav1.2."
FT /evidence="ECO:0000269|PubMed:17724025"
FT MUTAGEN 16
FT /note="H->A: Decrease in ability to inhibit both Nav1.4 and
FT Nav1.2, and potently decreases the binding affinity for
FT Nav1.2, Nav1.4, and Nav1.7."
FT /evidence="ECO:0000269|PubMed:17724025,
FT ECO:0000269|PubMed:21709136"
FT MUTAGEN 18
FT /note="R->A: Decrease in ability to inhibit both Nav1.4 and
FT Nav1.2, and the binding affinity for Nav1.2, Nav1.4, and
FT Nav1.7."
FT /evidence="ECO:0000269|PubMed:17724025,
FT ECO:0000269|PubMed:21709136"
FT NON_TER 1
FT /evidence="ECO:0000305|PubMed:23167564"
FT HELIX 11..16
FT /evidence="ECO:0007829|PDB:6J8E"
SQ SEQUENCE 22 AA; 2560 MW; 6FA5E01DA18BB629 CRC64;
KRNGCCNCSS KWCRDHSRCC GR
