KIIIA (P02587) Protein Card

General Information
Name KIIIA
Alternative name(s) K3a,KIIIA-P1
Organism Conus kinoshitai
Organism region Indo-Pacific
Organism diet piscivorous
Protein Type Wild type
Protein precursor KIIIA precursor (1694)
Notes

Block tetrodotoxin resistant (TTX-R) Na channels and the blockade is slow and reversible (Bulaj et al, 2005).

10 μM rapidly blocks A-fiber compound action potentials in mouse sciatic nerve. Also blocks C-fiber CAPs (Wilson and Zhang, 2015).

Disulfide bond connectivities of KIIIA (Khoo et al, 2012):

  • Native: [C1-C9,C2-C15,C4-C16]
  • Isomer 1: [C1-15,C2-C9,C4-C16]
  • Isomer 2: [C1-C16,C2-C9,C4-C15]
    		•

    Classification
    Conopeptide class conotoxin
    Gene superfamily M superfamily
    Cysteine framework III
    Pharmacological family mu conotoxin

    Sequence
    CCNCSSKWCRDHSRCC(nh2)
    Modified residues
    positionsymbolname
    17nh2C-term amidation
    Sequence evidence nucleic acid level
    Average Mass 1884.13
    Monoisotopic Mass 1882.63
    Isoelectric Point 11.73
    Extinction Coefficient [280nm] 5500.00

    Activity

    IC50: Voltage-Gated Sodium Channels

    TargetOrganismIC50nhillRef
    Nav1.2H. sapiens(KIIIA Isomer 1)124 nM+/-34Tran,H.N.T. et al. (2022)
    (KIIIA Isomer 2)1371 nM+/-403Tran,H.N.T. et al. (2022)
    (KIIIA Native)875 nM+/-129Tran,H.N.T. et al. (2022)
    R. norvegicus61nM+/-51.02Van Der Haegen,A. and Peigneur,S. and Tytgat,J. (2011)
    5nMMcArthur,J.R. et al. (2011)
    Nav1.3R. norvegicus8uM+/-1Zhang,M.M. et al. (2007)
    3.6uM+/-0.31.44Van Der Haegen,A. and Peigneur,S. and Tytgat,J. (2011)
    Nav1.4H. sapiens(KIIIA Isomer 1)65 nM+/-15Tran,H.N.T. et al. (2022)
    (KIIIA Isomer 2)2051 nM+/-482Tran,H.N.T. et al. (2022)
    (KIIIA Native)472 nM+/-94Tran,H.N.T. et al. (2022)
    R. norvegicus48nM+/-61.26Van Der Haegen,A. and Peigneur,S. and Tytgat,J. (2011)
    90nM+/-17Zhang,M.M. et al. (2007)
    54nMMcArthur,J.R. et al. (2011)
    Nav1.5H. sapiens>10uMVan Der Haegen,A. and Peigneur,S. and Tytgat,J. (2011)
    R. norvegicus287uM+/-40Zhang,M.M. et al. (2007)
    Nav1.6M. musculus240nM+/-30Wilson,M.J. et al. (2011)
    183nM+/-311.09Van Der Haegen,A. and Peigneur,S. and Tytgat,J. (2011)
    Nav1.7H. sapiens(KIIIA Isomer 1)413 nM+/-71Tran,H.N.T. et al. (2022)
    (KIIIA Isomer 2)5388 nM+/-547Tran,H.N.T. et al. (2022)
    (KIIIA Native)887 nM+/-295Tran,H.N.T. et al. (2022)
    R. norvegicus147nMMcArthur,J.R. et al. (2011)
    Nav1.8H. sapiens>10uMVan Der Haegen,A. and Peigneur,S. and Tytgat,J. (2011)

    Kd: Voltage-Gated Sodium Channels

    TargetOrganismKdRef
    Nav1.1R. norvegicus290nM+/-110Zhang,M.M. et al. (2007)
    Nav1.2R. norvegicus5nM+/-5Wilson,M.J. et al. (2011)
    3nMZhang,M.M. et al. (2007)
    0.005 uM+/-0.005Khoo,K.K. et al. (2009)
    5nMMcArthur,J.R. et al. (2011)
    Nav1.3R. norvegicus4.6uMZhang,M.M. et al. (2007)
    Nav1.4R. norvegicus50nMZhang,M.M. et al. (2007)
    37nMMcArthur,J.R. et al. (2011)
    Nav1.7R. norvegicus(+Nav?1)244nM+/-25Zhang,M.M. et al. (2013)
    (+Nav?3)420nM+/-60Zhang,M.M. et al. (2013)
    (+Nav?4)930nM+/-240Zhang,M.M. et al. (2013)
    97nMMcArthur,J.R. et al. (2011)
    (+Nav?2)1.38uM+/-0.03Zhang,M.M. et al. (2013)
    292nM+/-52Zhang,M.M. et al. (2013)
    290nM+/-90Zhang,M.M. et al. (2007)

    Percentage inhibition: Voltage-Gated Sodium Channels

    TargetOrganism% inhibitionConcentrationRef
    Nav1.2R. norvegicus90+/-31uMZhang,M.M. et al. (2007)
    Nav1.4R. norvegicus86+/-61uMZhang,M.M. et al. (2007)
    Nav TTX-RR. pipiens96+/-25uMZhang,M.M. et al. (2006)

    Synthetic variants
    KIIIA [D11A]CCNCSSKWCRAHSRCC(nh2)
    KIIIA [H12A]CCNCSSKWCRDASRCC(nh2)
    KIIIA [K7A]CCNCSSAWCRDHSRCC(nh2)
    KIIIA [K7NLeu]CCNCSS(Nle)WCRDHSRCC(nh2)
    KIIIA [N3A]CCACSSKWCRDHSRCC(nh2)
    KIIIA [R10A]CCNCSSKWCADHSRCC(nh2)
    KIIIA [R14A]CCNCSSKWCRDHSACC(nh2)
    KIIIA [S13A]CCNCSSKWCRDHARCC(nh2)
    KIIIA [S5A]CCNCASKWCRDHSRCC(nh2)
    KIIIA [S6A]CCNCSAKWCRDHSRCC(nh2)
    KIIIA [W8A]CCNCSSKACRDHSRCC(nh2)
    KIIIA [W8E]CCNCSSKECRDHSRCC(nh2)
    KIIIA [W8L]CCNCSSKLCRDHSRCC(nh2)
    KIIIA [W8Q]CCNCSSKQCRDHSRCC(nh2)
    KIIIA [W8R]CCNCSSKRCRDHSRCC(nh2)
    KIIIA [W8dTrp]CCNCSSKwCRDHSRCC(nh2)
    KIIIA-P2CCNCSSKWCRDHSRCC(nh2)
    KIIIA[C1A,C9A]ACNCSSKWARDHSRCC(nh2)
    KIIIA[C2A,C15A]CANCSSKWCRDHSRAC(nh2)
    KIIIA[C4A,C16A]CCNASSKWCRDHSRCA(nh2)
    KIIIA[Del1,S3/S4Aop,C9A]CNC(Aop)KWARDHARCC(nh2)

    References
    Bulaj,G., West,P.J., Garrett,J.E., Watkins,M., Zhang,M.M., Norton,R.S., Smith,B.J., Yoshikami,D. and Olivera,B.M. (2005) Novel conotoxins from Conus striatus and Conus kinoshitai selectively block TTX-resistant sodium channels Biochemistry 44:7259-7265
    Khoo,K.K., Feng,Z.P., Smith,B.J., Zhang,M.M., Yoshikami,D., Olivera,B.M., Bulaj,G. and Norton,R.S. (2009) Structure of the Analgesic mu-Conotoxin KIIIA and Effects on the Structure and Function of Disulfide Deletion. Biochemistry 6:1210-1219
    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. and Bulaj,G. (2007) Structure/function characterization of micro-conotoxin KIIIA, an analgesic, nearly irreversible blocker of mammalian neuronal sodium channels. J. Biol. Chem. 282:30699-30706
    McArthur,J.R., Singh,G., McMaster,D., Winkfein,R., Tieleman,D.P. and French,R.J. (2011) Interactions of key charged residues contributing to selective block of neuronal sodium channels by μ-conotoxin KIIIA. Mol. Pharmacol. 80:573-584
    Van Der Haegen,A., Peigneur,S. and Tytgat,J. (2011) Importance of position 8 in μ-conotoxin KIIIA for voltage-gated sodium channel selectivity. FEBS J. 278:3408-3418
    Zhang,M.M., Wilson,M.J., Azam,L., Gajewiak,J., Rivier,J.E., Bulaj,G., Olivera,B.M. and Yoshikami,D. (2013) Co-expression of Na(V)β subunits alters the kinetics of inhibition of voltage-gated sodium channels by pore-blocking μ-conotoxins. Br. J. Pharmacol. 168:1597-1610
    Wilson,M.J., Zhang,M.M., Gajewiak,J., Azam,L., Rivier,J.E., Olivera,B.M. and Yoshikami,D. (2015) α- and β-subunit composition of voltage-gated sodium channels investigated with μ-conotoxins and the recently discovered μO§-conotoxin GVIIJ. J Neurophysiol 113:2289-2301
    Khoo,K.K., Gupta,K., Green,B.R., Zhang,M.M., Watkins,M., Olivera,B.M., Balaram,P., Yoshikami,D., Bulaj,G. and Norton,R.S. (2012) Distinct disulfide isomers of μ-conotoxins KIIIA and KIIIB block voltage-gated sodium channels. Biochemistry 51:9826-9835
    Pan,X., Li,Z., Huang,X., Huang,G., Gao,S., Shen,H., Liu,L., Lei,J. and Yan,N. (2019) Molecular basis for pore blockade of human Na+ channel Nav1.2 by the μ-conotoxin KIIIA. Science eaaw2999
    Paul George,A.A., Heimer,P., Maaß,A., Hamaekers,J., Hofmann-Apitius,M., Biswas,A. and Imhof,D. (2018) Insights into the Folding of Disulfide-Rich μ-Conotoxins ACS Omega 3:12330-12340
    Meng,G., Kuyucak,S. (2022) Computational Design of High-Affinity Blockers for Sodium Channel NaV1.2 from µ-Conotoxin KIIIA. Mar Drugs 20:154
    Tran,H.N.T., McMahon,K.L., Deuis,J.R., Vetter,I., Schroeder,C.I. (2022) Structural and functional insights into the inhibition of human voltage-gated sodium channels by µ-conotoxin KIIIA disulfide isomers. J Biol Chem 298:101728

    Internal links
    Protein Precursor KIIIA precursor (1694)
    Nucleic acids
    Structure NMR solution structure of an analgesic Mu-contoxin KIIIA
    NMR solution structure of Mu-conotoxin KIIIA
    Human Nav1.2-beta2-KIIIA ternary complex
    Mu-conotoxin KIIIA isomer 2
    KIIIA Native

    External links
    Ncbi 2LXG_A

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