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).

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. norvegicus500pM0.8300uM AchCartier,G.E. et al. (1996)
2.18nM0.75100uM AchMcIntosh,J.M. et al. (2004)
3.0nM+/-0.91uM nicotinePucci,L. et al. (2011)
3.7nM+/-0.31.370uM AchEverhart,D. et al. (2004)
Unknown6.1nM1.38100uM AchDutertre,S. et al. (2005)
3.5nM1.35AchHarvey,S.C. et al. (1997)
α4β2Unknown548.4nM0.97100uM AchDutertre,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 [lateral caudate])310pM0.5 nM 125I-alpha-conotoxin-MIIBordia,T. et al. (2007)
(Autoradiography of striatum [medial caudate])230pM 0.5 nM 125I-alpha-conotoxin-MIIBordia,T. et al. (2007)
(Autoradiography of striatum [ventral putamen])260pM 0.5 nM 125I-alpha-conotoxin-MIIBordia,T. et al. (2007)
(Autoradiography of striatum [dorsal putamen])270pM 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(oocyte)218nM 0.1nM epibatidinePucci,L. et al. (2011)
(HEK cell)255nM0.1nM 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-MIICLNSHELHCVPNSCCG(Ada)
MII [E11A,L15A](nh2)CANSHALHCVPNSCCG
MII [E11A](nh2)CLNSHALHCVPNSCCG
MII [E11R](nh2)CLNSHRLHCVPNSCCG
MII [G1A](nh2)CLNSHELHCVPNSCCA
MII [H12A](nh2)CLNSAELHCVPNSCCG
MII [H9A,L15A](nh2)CANSHELACVPNSCCG
MII [H9A](nh2)CLNSHELACVPNSCCG
MII [L10A,L15A](nh2)CANSHEAHCVPNSCCG
MII [L10A](nh2)CLNSHEAHCVPNSCCG
MII [L15A](nh2)CANSHELHCVPNSCCG
MII [N14A](nh2)CLASHELHCVPNSCCG
MII [N5A](nh2)CLNSHELHCVPASCCG
MII [N5Ada]CLNSHELHCVP(Ada)SCCG
MII [P6A](nh2)CLNSHELHCVANSCCG
MII [S13A](nh2)CLNAHELHCVPNSCCG
MII [S4A,E11A,L15A](nh2)CANSHALHCVPNACCG
MII [S4A,H9A](nh2)CLNSHELACVPNACCG
MII [S4A](nh2)CLNSHELHCVPNACCG
MII [V7A](nh2)CLNSHELHCAPNSCCG
RDP-MII(nh2)CLNSHELHCVPNSCCGPDR
RDP-MII [E11R](nh2)CLNSHRLHCVPNSCCGPDR
RDP-MII [R1ADMA](nh2)CLNSHELHCVPNSCCGPD(ADMA)
cMII-6GGAAGGCLNSHELHCVPNSCCG
cMII-7GAAGGAGCLNSHELHCVPNSCCG

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
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

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 2211312A, 1MII_A, 1M2C_A

Tools