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P0C195

- CM3A_CONKI

UniProt

P0C195 - CM3A_CONKI

Protein

Mu-conotoxin KIIIA

Gene
N/A
Organism
Conus kinoshitai (Kinoshita's cone)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at transcript leveli
  1. Functioni

    Mu-conotoxins block voltage-gated sodium channels (Nav). This toxin potently blocks rNav1.2/SCN2A and rNav1.4/SCN4A. It also moderately blocks rNav1.1/SCN1A, rNav1.3/SCN3A, rNav1.5/SCN5A, mNav1.6/SCN8A, and rNav1.7/SCN9A. On rNav1.2/SCN2A, it produces a block that is only partially reversible. The block of SCN9A is modified when beta-subunits are coexpressed with the alpha subunit. Hence, blocks of channels containing beta-1 and beta-3 subunits are more potent (compared to channels without beta subunits), whereas blocks of channels containing beta-2 and beta-4 subunits are less potent (compared to channels without beta subunits).7 Publications

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sitei7 – 71Key residue in the pharmacophore, alpha-helical region
    Sitei8 – 81Key residue in the pharmacophore, alpha-helical region
    Sitei10 – 101Key residue in the pharmacophore, alpha-helical region
    Sitei11 – 111Key residue in the pharmacophore, alpha-helical region
    Sitei12 – 121Key residue in the pharmacophore, alpha-helical region
    Sitei14 – 141Key residue in the pharmacophore

    Keywords - Molecular functioni

    Ion channel impairing toxin, Neurotoxin, Toxin, Voltage-gated sodium channel impairing toxin

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Mu-conotoxin KIIIA
    OrganismiConus kinoshitai (Kinoshita's cone)
    Taxonomic identifieri376876 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaLophotrochozoaMolluscaGastropodaCaenogastropodaHypsogastropodaNeogastropodaConoideaConidaeConus

    Organism-specific databases

    ConoServeri1694. KIIIA precursor.

    Subcellular locationi

    Secreted By similarity

    GO - Cellular componenti

    1. extracellular region Source: UniProtKB-SubCell

    Keywords - Cellular componenti

    Secreted

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi1 – 11C → A: Structure similar to wild-type toxin, even with this disulfide bond deletion. 1 Publication
    Mutagenesisi7 – 71K → A: Attenuates the activity against rNav1.4/SCN4A but not rNav1.2/SCN2A. 2 Publications
    Mutagenesisi8 – 81W → A: Attenuates the activity against both rNav1.4/SCN4A and rNav1.2/SCN2A. Attenuates the binding affinity of rNav1.2/SCN2A, rNav1.4/SCN2A, and rNav1.7/SCN9A. 2 Publications
    Mutagenesisi8 – 81W → E: 200-fold reduction of activity toward rNav1.4/SCN4A. Block of rNav1.2/SCN2A is completely reversible. 2 Publications
    Mutagenesisi8 – 81W → Q: 70-fold reduction of activity toward rNav1.4/SCN4A. Block of rNav1.2/SCN2A is completely reversible. 2 Publications
    Mutagenesisi8 – 81W → R: 40-fold reduction of activity toward rNav1.4/SCN4A. Block of rNav1.2/SCN2A is completely reversible. 2 Publications
    Mutagenesisi9 – 91C → A: Structure similar to wild-type toxin, even with this disulfide bond deletion. 1 Publication
    Mutagenesisi10 – 101R → A: Attenuates the activity against both rNav1.4/SCN4A and rNav1.2/SCN2A, and the binding affinity of rNav1.2/SCN2A, rNav1.4/SCN4A, and rNav1.7/SCN9A. 2 Publications
    Mutagenesisi11 – 111D → A: Attenuates the activity against both rNav1.4/SCN4A and rNav1.2/SCN2A. 1 Publication
    Mutagenesisi12 – 121H → A: Attenuates the activity against both rNav1.4/SCN4A and rNav1.2/SCN2A, and potently decreases the binding affinity of rNav1.2/SCN2A, rNav1.4/SCN4A, and rNav1.7/SCN9A. 2 Publications
    Mutagenesisi14 – 141R → A: Attenuates the activity against both rNav1.4/SCN4A and rNav1.2/SCN2A, and the binding affinity of rNav1.2/SCN2A, rNav1.4/SCN4A, and rNav1.7/SCN9A. 2 Publications

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Peptidei1 – 1616Mu-conotoxin KIIIAPRO_0000232662Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Disulfide bondi1 ↔ 91 Publication
    Disulfide bondi2 ↔ 151 Publication
    Disulfide bondi4 ↔ 161 Publication
    Modified residuei16 – 161Cysteine amide

    Keywords - PTMi

    Amidation, Disulfide bond

    Expressioni

    Tissue specificityi

    Expressed by the venom duct.

    Interactioni

    Subunit structurei

    Monomer.1 Publication

    Structurei

    Secondary structure

    1
    18
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Helixi7 – 126

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    2LXGNMR-A1-16[»]
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domaini

    The cysteine framework is III (CC-C-C-CC). Classified in the M-5 branch, since 5 residues stand between the fourth and the fifth cysteine residues.

    Sequence similaritiesi

    Belongs to the conotoxin M superfamily.Curated

    Sequencei

    Sequence statusi: Complete.

    Sequence processingi: The displayed sequence is further processed into a mature form.

    P0C195-1 [UniParc]FASTAAdd to Basket

    « Hide

    CCNCSSKWCR DHSRCCGR                                      18
    Length:18
    Mass (Da):2,104
    Last modified:April 18, 2006 - v1
    Checksum:i6FA593BD458C3C39
    GO

    Cross-referencesi

    Web resourcesi

    Biological Magnetic Resonance Data Bank

    Mu-conotoxin KIIIA entry

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    Entry Method Resolution (Å) Chain Positions PDBsum
    2LXG NMR - A 1-16 [» ]
    ModBasei Search...
    MobiDBi Search...

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Organism-specific databases

    ConoServeri 1694. KIIIA precursor.

    Family and domain databases

    ProtoNeti Search...

    Publicationsi

    1. "Novel conotoxins from Conus striatus and Conus kinoshitai selectively block TTX-resistant sodium channels."
      Bulaj G., West P.J., Garrett J.E., Watkins M., Zhang M.-M., Norton R.S., Smith B.J., Yoshikami D., Olivera B.M.
      Biochemistry 44:7259-7265(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA], SYNTHESIS OF 1-16, FUNCTION.
      Tissue: Venom duct.
    2. "Structure/function characterization of mu-conotoxin KIIIA, an analgesic, nearly irreversible blocker of mammalian neuronal sodium channels."
      Zhang M.-M., Green B.R., Catlin P., Fiedler B., Azam L., Chadwick A., Terlau H., McArthur J.R., French R.J., Gulyas J., Rivier J.E., Smith B.J., Norton R.S., Olivera B.M., Yoshikami D., Bulaj G.
      J. Biol. Chem. 282:30699-30706(2007) [PubMed] [Europe PMC] [Abstract]
      Cited for: SYNTHESIS OF 1-16, FUNCTION, MUTAGENESIS OF LYS-7; TRP-8; ARG-10; ASP-11; HIS-12 AND ARG-14.
    3. "Pruning nature: biodiversity-derived discovery of novel sodium channel blocking conotoxins from Conus bullatus."
      Holford M., Zhang M.-M., Gowd K.H., Azam L., Green B.R., Watkins M., Ownby J.-P., Yoshikami D., Bulaj G., Olivera B.M.
      Toxicon 53:90-98(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: SYNTHESIS OF 1-16, FUNCTION.
    4. "Importance of position 8 in mu-conotoxin KIIIA for voltage-gated sodium channel selectivity."
      Van Der Haegen A., Peigneur S., Tytgat J.
      FEBS J. 278:3408-3418(2011) [PubMed] [Europe PMC] [Abstract]
      Cited for: SYNTHESIS OF 1-16, FUNCTION, MUTAGENESIS OF TRP-8.
    5. "Interactions of key charged residues contributing to selective block of neuronal sodium channels by mu-conotoxin KIIIA."
      McArthur J.R., Singh G., McMaster D., Winkfein R., Tieleman D.P., French R.J.
      Mol. Pharmacol. 80:573-584(2011) [PubMed] [Europe PMC] [Abstract]
      Cited for: SYNTHESIS OF 1-16, FUNCTION, MUTAGENESIS OF LYS-7; ARG-10; HIS-12 AND ARG-14.
    6. "mu-Conotoxins that differentially block sodium channels Nav1.1 through 1.8 identify those responsible for action potentials in sciatic nerve."
      Wilson M.J., Yoshikami D., Azam L., Gajewiak J., Olivera B.M., Bulaj G., Zhang M.M.
      Proc. Natl. Acad. Sci. U.S.A. 108:10302-10307(2011) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION ON SODIUM CHANNELS, SYNTHESIS.
    7. "Co-expression of Na(V)beta subunits alters the kinetics of inhibition of voltage-gated sodium channels by pore-blocking mu-conotoxins."
      Zhang M.M., Wilson M.J., Azam L., Gajewiak J., Rivier J.E., Bulaj G., Olivera B.M., Yoshikami D.
      Br. J. Pharmacol. 168:1597-1610(2013) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION ON SODIUM CHANNELS.
    8. "Structure of the analgesic mu-conotoxin KIIIA and effects on the structure and function of disulfide deletion."
      Khoo K.K., Feng Z.-P., Smith B.J., Zhang M.-M., Yoshikami D., Olivera B.M., Bulaj G., Norton R.S.
      Biochemistry 48:1210-1219(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: STRUCTURE BY NMR OF 1-16, SYNTHESIS OF 1-16, SUBUNIT, MUTAGENESIS OF CYS-1 AND CYS-9, DISULFIDE BOND.

    Entry informationi

    Entry nameiCM3A_CONKI
    AccessioniPrimary (citable) accession number: P0C195
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: April 18, 2006
    Last sequence update: April 18, 2006
    Last modified: October 1, 2014
    This is version 28 of the entry and version 1 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programAnimal Toxin Annotation Program

    Miscellaneousi

    Miscellaneous

    Has no effect on hNav1.5/SCN5A and hNav1.8/SCN10A.1 Publication

    Keywords - Technical termi

    3D-structure

    Documents

    1. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    2. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3