MII (P00039) Protein Card

General Information
Name MII
Organism Conus magus (Magus cone)
Organism region Indo-Pacific
Organism diet piscivorous
Protein Type Wild type
Protein precursor MII precursor (8)
Notes
  • Does not inhibit the N-type calcium channel via GABAB (Klimis et al. 2011) but has strong anti-allodynic actions upon intrathecal injection (Napier 2012).

  • Osipov et al., 2020 reported that MII increases the cytotoxic effect of indomethacin 1.9-fold after 48 h of cultivation, and inhibits Ehrlich carcinoma growth and increase mouse survival.

  • MII promotes the proliferation of glioma C6 cells (Terpinskaya et al., 2021).

  • Classification
    Conopeptide class conotoxin
    Gene superfamily A superfamily
    Cysteine framework I
    Pharmacological family alpha conotoxin

    Sequence
    GCCSNPVCHLEHSNLC(nh2)
    Modified residues
    positionsymbolname
    17nh2C-term amidation
    Sequence evidence protein level
    Average Mass 1710.93
    Monoisotopic Mass 1709.65
    Isoelectric Point 6.81
    Extinction Coefficient [280nm] NA

    Activity

    IC50: Nicotinic acetylcholine receptors

    TargetOrganismIC50nhillCompetitorAgonistRef
    α3β2H. sapiens4.4nM+/-1.21uM nicotinePucci,L. et al. (2011)
    R. norvegicus4.2 nM-0.887ACh (100 μM)Beissner,M. et al. (2012)
    3.0nM+/-0.91uM nicotinePucci,L. et al. (2011)
    (mutant ô°€α3(I186R)ô°β2)58.3 nM[45.1-75.5]-1.327ACh (100 μM)Beissner,M. et al. (2012)
    3.7nM+/-0.31.370uM AchEverhart,D. et al. (2004)
    500pM0.8300uM AchCartier,G.E. et al. (1996)
    2.18nM0.75100uM AchMcIntosh,J.M. et al. (2004)
    Unknown3.5nM1.35AchHarvey,S.C. et al. (1997)
    6.08 nM[4.87-7.61]1.38Ach (100 uM)Dutertre,S. et al. (2005)
    α4β2R. norvegicus(mutant ô°€α4(T147S)ô°β2)3206 nM[2538-4050]-0.903ACh (100 μM)Beissner,M. et al. (2012)
    3293 nM[2855-3798]-0.852ACh (100 μM)Beissner,M. et al. (2012)
    (mutant ô°€α4(A191E)ô°β2)1938 nM[1683-2233]-0.996ACh (100 μM)Beissner,M. et al. (2012)
    (mutant ô°€α4(R185I)ô°β2)192.8 nM[158-236]-1.058ACh (100 μM)Beissner,M. et al. (2012)
    (mutant ô°€α4(E188N)ô°β2)3766 nM[3253-4361]-1.03ACh (100 μM)Beissner,M. et al. (2012)
    Unknown548.40 nM[400.6-750.7]0.97Ach (100 uM)Dutertre,S. et al. (2005)
    α6/α3β2β3R. norvegicus390pM0.53100uM AchMcIntosh,J.M. et al. (2004)
    α6/α3β4H. sapiens1.49 nM[1.18-1.88]300 uM AChHone,A.J. et al. (2021)
    R. norvegicus31.5 nM[29.2-33.9]300 uM AChHone,A.J. et al. (2021)
    α9α10Unknown>1uM30uM AchKlimis,H. et al. (2011)
    a7*α6β2*R. norvegicus4.4nM1uM nicotinePucci,L. et al. (2011)
    S. sciureus(Autoradiography of striatum [dorsal putamen])270pM[200-360] 0.5 nM 125I-alpha-conotoxin-MIIBordia,T. et al. (2007)
    (Autoradiography of striatum [medial caudate])230pM[180-310] 0.5 nM 125I-alpha-conotoxin-MIIBordia,T. et al. (2007)
    (Autoradiography of striatum [lateral caudate])310pM[250-390]0.5 nM 125I-alpha-conotoxin-MIIBordia,T. et al. (2007)
    (Autoradiography of striatum [ventral putamen])260pM[220-300] 0.5 nM 125I-alpha-conotoxin-MIIBordia,T. et al. (2007)

    Kd: Nicotinic acetylcholine receptors

    TargetOrganismKdRef
    α3β2R. norvegicus2.32nMShiembob,D.L. et al. (2006)

    Ki: Nicotinic acetylcholine receptors

    TargetOrganismKiCompetitorAgonistRef
    α3β2H. sapiens( 0.1nM epibatidine)218nM 0.1nM epibatidinePucci,L. et al. (2011)
    (0.1nM epibatidine)255nM0.1nM epibatidinePucci,L. et al. (2011)
    R. norvegicus(0.1nM epibatidine)261nM0.1nM epibatidinePucci,L. et al. (2011)
    α3β2*R. norvegicus(0.1nM epibatidine)62nM0.1nM epibatidinePucci,L. et al. (2011)
    a7*α6β2*R. norvegicus(0.1nM epibatidine)5.6nM0.1nM epibatidinePucci,L. et al. (2011)
    (0.1nM epibatidine)8uM0.1nM epibatidinePucci,L. et al. (2011)

    Percentage inhibition: Nicotinic acetylcholine receptors

    TargetOrganism% inhibitionConcentrationAgonistRef
    α1β1γδM. musculus11+/-3200nM1uM AchCartier,G.E. et al. (1996)
    α2β2R. norvegicus20+/-3200nM300uM AchCartier,G.E. et al. (1996)
    Unknown0+/-50AchHarvey,S.C. et al. (1997)
    α2β4R. norvegicus4+/-6200nM300uM AchCartier,G.E. et al. (1996)
    α3β4R. norvegicus15+/-5200nM300uM AchCartier,G.E. et al. (1996)
    Unknown0+/-50AchHarvey,S.C. et al. (1997)
    α4β2R. norvegicus30+/-1200nM300uM AchCartier,G.E. et al. (1996)
    Unknown0+/-50AchHarvey,S.C. et al. (1997)
    α4β4R. norvegicus4+/-1200nM300uM AchCartier,G.E. et al. (1996)
    α7R. norvegicus56+/-8200nM1mM AchCartier,G.E. et al. (1996)
    α9α10Unknown03uM30uM AchKlimis,H. et al. (2011)

    Synthetic variants
    Ada-MII(Ada)GCCSNPVCHLEHSNLC
    MII [E11A,L15A]GCCSNPVCHLAHSNAC(nh2)
    MII [E11A]GCCSNPVCHLAHSNLC(nh2)
    MII [E11R]GCCSNPVCHLRHSNLC(nh2)
    MII [G1A]ACCSNPVCHLEHSNLC(nh2)
    MII [H12A]GCCSNPVCHLEASNLC(nh2)
    MII [H9A,L15A]GCCSNPVCALEHSNAC(nh2)
    MII [H9A]GCCSNPVCALEHSNLC(nh2)
    MII [L10A,L15A]GCCSNPVCHAEHSNAC(nh2)
    MII [L10A]GCCSNPVCHAEHSNLC(nh2)
    MII [L15A]GCCSNPVCHLEHSNAC(nh2)
    MII [N14A]GCCSNPVCHLEHSALC(nh2)
    MII [N5A]GCCSAPVCHLEHSNLC(nh2)
    MII [N5Ada]GCCS(Ada)PVCHLEHSNLC
    MII [P6A]GCCSNAVCHLEHSNLC(nh2)
    MII [S13A]GCCSNPVCHLEHANLC(nh2)
    MII [S4A,E11A,L15A]GCCANPVCHLAHSNAC(nh2)
    MII [S4A,H9A]GCCANPVCALEHSNLC(nh2)
    MII [S4A]GCCANPVCHLEHSNLC(nh2)
    MII [V7A]GCCSNPACHLEHSNLC(nh2)
    RDP-MIIRDPGCCSNPVCHLEHSNLC(nh2)
    RDP-MII [E11R]RDPGCCSNPVCHLRHSNLC(nh2)
    RDP-MII [R1ADMA](ADMA)DPGCCSNPVCHLEHSNLC(nh2)
    cMII-6GCCSNPVCHLEHSNLCGGAAGG
    cMII-7GCCSNPVCHLEHSNLCGAGGAAG

    References
    Cartier,G.E., Yoshikami,D., Gray,W.R., Luo,S., Olivera,B.M. and McIntosh,J.M. (1996) A new alpha-conotoxin which targets alpha3beta2 nicotinic acetylcholine receptors J. Biol. Chem. 271:7522-7528
    Shon,K.J., Koerber,S.C., Rivier,J.E., Olivera,B.M. and McIntosh,J.M. (1997) Three-dimensional solution structure of alpha-conotoxin MII, an alpha3beta2 neuronal nicotinic acetylcholine receptor-targeted ligand Biochemistry 36:15693-15700
    Hill,J.M., Oomen,C.J., Miranda,L.P., Bingham,J.P., Alewood,P.F. and Craik,D.J. (1998) Three-dimensional solution structure of alpha-conotoxin MII by NMR spectroscopy: effects of solution environment on helicity Biochemistry 37:15621-15630
    Everhart,D., Cartier,G.E., Malhotra,A., Gomes,A.V., McIntosh,J.M. and Luetje,C.W. (2004) Determinants of potency on alpha-conotoxin MII, a peptide antagonist of neuronal nicotinic receptors Biochemistry 43:2732-2737
    Pucci,L., Grazioso,G., Dallanoce,C., Rizzi,L., De Micheli,C., Clementi,F., Bertrand,S., Bertrand,D., Longhi,R., De Amici,M. and Gotti,C. (2011) Engineering of α-conotoxin MII-derived peptides with increased selectivity for native α6β2* nicotinic acetylcholine receptors. FASEB J. 25:3775-3789
    McIntosh,J.M., Azam,L., Staheli,S., Dowell,C., Lindstrom,J.M., Kuryatov,A., Garrett,J.E., Marks,M.J. and Whiteaker,P. (2004) Analogs of alpha-conotoxin MII are selective for alpha6-containing nicotinic acetylcholine receptors. Mol. Pharmacol. 65:944-952
    Klimis,H., Adams,D.J., Callaghan,B., Nevin,S., Alewood,P.F., Vaughan,C.W., Mozar,C.A. and Christie,M.J. (2011) A novel mechanism of inhibition of high-voltage activated calcium channels by α-conotoxins contributes to relief of nerve injury-induced neuropathic pain. Pain 152:259-266
    Harvey,S.C., McIntosh,J.M., Cartier,G.E., Maddox,F.N. and Luetje,C.W. (1997) Determinants of specificity for alpha-conotoxin MII on alpha3beta2 neuronal nicotinic receptors. Mol. Pharmacol. 51:336-342
    Dutertre,S., Nicke,A., and Lewis,R.J. (2005) Beta2 subunit contribution to 4/7 alpha-conotoxin binding to the nicotinic acetylcholine receptor. J. Biol. Chem. 280:30460-30468
    Napier,I.A., Klimis,H., Rycroft,B.K., Jin,A.H., Alewood,P.F., Motin,L., Adams,D.J. and Christie,M.J. (2012) Intrathecal α-conotoxins Vc1.1, AuIB and MII acting on distinct nicotinic receptor subtypes reverse signs of neuropathic pain. Neuropharmacology 62:2202-2207
    Kapono,C.A., Thapa,P., Cabalteja,C.C., Guendisch,D., Collier,A.C. and Bingham,J.P. (2013) Conotoxin truncation as a post-translational modification to increase the pharmacological diversity within the milked venom of Conus magus. Toxicon
    Bordia,T., Grady,S.R., McIntosh,J.M. and Quik,M. (2007) Nigrostriatal damage preferentially decreases a subpopulation of alpha6beta2* nAChRs in mouse, monkey, and Parkinson Mol. Pharmacol. 72:52-61
    Osipov,A.V., Terpinskaya,T.I., Yanchanka,T., Balashevich,T., Zhmak,M.N., Tsetlin,V.I. and Utkin,Y.N (2020) α-Conotoxins Enhance both the In Vivo Suppression of Ehrlich carcinoma Growth and In Vitro Reduction in Cell Viability Elicited by Cyclooxygenase and Lipoxygenase Inhibitors Mar Drugs 18
    Beissner,M., Dutertre,S., Schemm,R., Danker,T., Sporning,A., Grubmüller,H. and Nicke,A. (2012) Efficient binding of 4/7 α-conotoxins to nicotinic α4β2 receptors is prevented by Arg185 and Pro195 in the α4 subunit Mol. Pharmacol 82:711-718
    Hone,A.J., Kaas,Q., Kearns,I., Hararah,F., Gajewiak,J., Christensen,S., Craik,D.J. and McIntosh,J.M. (2021) Computational and Functional Mapping of Human and Rat α6β4 Nicotinic Acetylcholine Receptors Reveals Species-Specific Ligand-Binding Motifs. J Med Chem 64:1685-1700
    Terpinskaya,T.I., Osipov,A.V., Kryukova,E.V., Kudryavtsev,D.S., Kopylova,N.V., Yanchanka,T.L., Palukoshka,A.F., Gondarenko,E.A., Zhmak,M.N., Tsetlin,V.I. and Utkin,Y.N. (2021) α-Conotoxins and α-Cobratoxin Promote, while Lipoxygenase and Cyclooxygenase Inhibitors Suppress the Proliferation of Glioma C6 Cells. Mar Drugs 19

    Internal links
    Protein Precursor MII precursor (8)
    Nucleic acids
    Structure THREE-DIMENSIONAL STRUCTURE OF ALPHA-CONOTOXIN MII, NMR, 14 STRUCTURES
    SOLUTION STRUCTURE OF ALPHA-CONOTOXIN MII

    External links
    Ncbi 1M2C_A, 1MII_A, 2211312A

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