MII (P00039) Protein Card

General Information
Name MII
Alternative name(s) Ca004
Organism Conus magus (Magus cone)
Conus catus
Organism region Indo-Pacific,Indo-Pacific
Organism diet piscivorous,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.


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. norvegicus3.7nM+/-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)
3.0nM+/-0.91uM nicotinePucci,L. et al. (2011)
4.2 nM-0.887ACh (100 μM)Beissner,M. et al. (2012)
(mutant 􏰀α3(I186R)􏰁β2)58.3 nM[45.1-75.5]-1.327ACh (100 μM)Beissner,M. et al. (2012)
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 􏰀α4(T147S)􏰁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 􏰀α4(E188N)􏰁β2)3766 nM[3253-4361]-1.03ACh (100 μM)Beissner,M. et al. (2012)
(mutant 􏰀α4(A191E)􏰁β2)1938 nM[1683-2233]-0.996ACh (100 μM)Beissner,M. et al. (2012)
(mutant 􏰀α4(R185I)􏰁β2)192.8 nM[158-236]-1.058ACh (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)
α9α10Unknown>1uM30uM AchKlimis,H. et al. (2011)
a7*α6β2*R. norvegicus4.4nM1uM nicotinePucci,L. et al. (2011)
S. sciureus(Autoradiography of striatum [ventral putamen])260pM[220-300] 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 [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)

Kd: Nicotinic acetylcholine receptors

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

Ki: Nicotinic acetylcholine receptors

TargetOrganismKiCompetitorAgonistRef
α3β2H. sapiens(HEK cell)255nM0.1nM epibatidinePucci,L. et al. (2011)
(oocyte)218nM 0.1nM epibatidinePucci,L. et al. (2011)
R. norvegicus(oocyte)261nM0.1nM epibatidinePucci,L. et al. (2011)
α3β2*R. norvegicus62nM0.1nM epibatidinePucci,L. et al. (2011)
a7*α6β2*R. norvegicus(Low affinity site)8uM0.1nM epibatidinePucci,L. et al. (2011)
(High affinity site)5.6nM0.1nM 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
Himaya, S.W.A., Jin, A.H., Dutertre, S., Giacomotto, J., Mohialdeen, H., Vetter, I., Alewood, P.F. and Lewis, R.J. (2015) Comparative venomics reveals the complex prey capture strategy of the piscivorous cone snail Conus catus. Journal of proteome research 14:4372-4381
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

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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