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P0C195

- CM3A_CONKI

UniProt

P0C195 - CM3A_CONKI

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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

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-KW
Complete GO annotation...

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 – 126Combined sources

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
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

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        10 
CCNCSSKWCR DHSRCCGR
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:
PDBei
RCSB PDBi
PDBji
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: November 26, 2014
This is version 30 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