MI (P00023) Protein Card

General Information

Name	MI
Alternative name(s)	M1
Organism	Conus magus (Magus cone)
Organism region	Indo-Pacific
Organism diet	piscivorous
Protein Type	Wild type
Notes	MI binds at the alpha/delta interface of the muscle type nAChR (Sine et al. 1995; Cortez et al. 2007). This toxin was used to study the specific opening patterns elicited by agonist binding at either the alpha-gamma, alpha-deta and alpha-epsilon interface (Stock et al. 2014; Dudel et al. 2014) The dose of 40 µg/kg of MI resulted in a death rate of 100% in mice after 1186 +/- 168 seconds (Ma et al. 2021).

Classification

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

Sequence

GRCCHPACGKNYSC(nh2)

Modified residues

position	symbol	name
15	nh2	C-term amidation

Sequence evidence

protein level

Average Mass

1493.71

Monoisotopic Mass

1492.56

Isoelectric Point

11.81

Extinction Coefficient [280nm]

1490.00

Activity

IC50: Nicotinic acetylcholine receptors

Target	Organism	IC50		Agonist	Ref
α1β1δ	M. musculus	400pM	+/-170	1-10uM Ach	Jacobsen,R.B. et al. (1999)
α1β1γδ	M. musculus	12nM		500nM Ach	Johnson,D.S. et al. (1995)
		400pM	+/-10	1-10uM Ach	Jacobsen,R.B. et al. (1999)
	R. norvegicus	7.0 nM	[5.6-8.8]	200 uM ACh	Ma X et al. (2021)
α1β1;γ	M. musculus	18uM	+/-5	1-10uM Ach	Jacobsen,R.B. et al. (1999)
α2β2	R. norvegicus	>5uM		300uM Ach	Johnson,D.S. et al. (1995)
α2β4	R. norvegicus	>5uM		300uM Ach	Johnson,D.S. et al. (1995)
α3β2	R. norvegicus	>5uM		300uM Ach	Johnson,D.S. et al. (1995)
α3β4	R. norvegicus	>5uM		300uM Ach	Johnson,D.S. et al. (1995)
α4β2	R. norvegicus	>5uM		300uM Ach	Johnson,D.S. et al. (1995)
α4β4	R. norvegicus	>5uM		300uM Ach	Johnson,D.S. et al. (1995)
α7	R. norvegicus	>5uM		500uM Ach	Johnson,D.S. et al. (1995)
α9	R. norvegicus	>5uM		100uM Ach	Johnson,D.S. et al. (1995)

Kd: Nicotinic acetylcholine receptors

Target	Organism	Kd		Ref
α1β1γδ	M. musculus	1.4nM	+/-0.1	Jacobsen,R.B. et al. (1999)

Ki: Nicotinic acetylcholine receptors

Target	Organism	Ki		Competitor	Ref
α1β1γδ	T. californica	89.1nM	+/-9.1	2nM [3H]epibatidine	Kapono,C.A. et al. (2013)
α3β4*	S. scrofa	>5uM		0.5 nM [3H]epibatidine	Kapono,C.A. et al. (2013)
α4β2*	R. norvegicus	>10uM		0.5 nM [3H]epibatidine	Kapono,C.A. et al. (2013)

Synthetic variants

MI [H5A]	GRCCAPACGKNYSC(nh2)
MI [K10A]	GRCCHPACGANYSC(nh2)
MI [N11A]	GRCCHPACGKAYSC(nh2)
MI [P6A]	GRCCHAACGKNYSC(nh2)
MI [R2A]	GACCHPACGKNYSC(nh2)
MI [S13A]	GRCCHPACGKNYAC(nh2)
MI [Y12A]	GRCCHPACGKNASC(nh2)
MI [Y12Dit]	GRCCHPACGKN(Dit)SC(nh2)
MI [Y12H]	GRCCHPACGKNHSC(nh2)
MI [Y12M]	GRCCHPACGKNMSC(nh2)
MI [Y12W]	GRCCHPACGKNWSC(nh2)
MI [not amidated]	GRCCHPACGKNYSC
MIC	CCHPACGKNYSC(nh2)
MI[del1]	RCCHPACGKNYSC(nh2)
MI[del9]	GRCCHPACKNYSC(nh2)
MI[ins14_A]	GRCCHPACGKNYSAC(nh2)
MI[ins14_KA]	GRCCHPACGKNYSKAC(nh2)
MI[ins14_K]	GRCCHPACGKNYSKC(nh2)
MI[ins14_RA]	GRCCHPACGKNYSRAC(nh2)
MI[ins14_R]	GRCCHPACGKNYSRC(nh2)

References

McIntosh,M., Cruz,L.J., Hunkapiller,M.W., Gray,W.R. and Olivera,B.M. (1982) Isolation and structure of a peptide toxin from the marine snail Conus magus Arch. Biochem. Biophys. 218:329-334

Gray,W.R., Rivier,J.E., Galyean,R., Cruz,L.J. and Olivera,B.M. (1983) Conotoxin MI. Disulfide bonding and conformational states J. Biol. Chem. 258:12247-12251

Jacobsen,R.B., DelaCruz,R.G., Grose,J.H., McIntosh,J.M., Yoshikami,D. and Olivera,B.M. (1999) Critical residues influence the affinity and selectivity of alpha-conotoxin MI for nicotinic acetylcholine receptors Biochemistry 38:13310-13315

Johnson,D.S., Martinez,J., Elgoyhen,A.B., Heinemann,S.F. and McIntosh,J.M. (1995) alpha-Conotoxin ImI exhibits subtype-specific nicotinic acetylcholine receptor blockade: preferential inhibition of homomeric alpha 7 and alpha 9 receptors Mol. Pharmacol. 48:194-199

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

Cortez,L., Marino-Buslje,C., de Jiménez Bonino,M.B. and Hellman,U. (2007) Interactions between alpha-conotoxin MI and the Torpedo marmorata receptor alpha-delta interface. Biochem. Biophys. Res. Commun. 355:275-279

Sine,S.M., Kreienkamp,H.J., Bren,N., Maeda,R. and Taylor,P. (1995) Molecular dissection of subunit interfaces in the acetylcholine receptor: identification of determinants of alpha-conotoxin M1 selectivity. Neuron 15:205-211

Dudel,J. (2014) α-Conotoxin M1 (CTx) blocks αδ binding sites of adult nicotinic receptors while ACh binding at αε sites elicits only small and short quantal synaptic currents. Physiol Rep 2

Stock,P., Ljaschenko,D., Heckmann,M. and Dudel,J. (2014) Agonists binding nicotinic receptors elicit specific channel-opening patterns at αÎ³ and αÎ´ sites. J. Physiol. (Lond.) 592:2501-2517

Ma X, Huang Q, Yu S, Xu S, Huang Y, Zhao Z, Xiao X, Dai Q. (2021) The 3/4- and 3/6-Subfamily Variants of α-Conotoxins GI and MI Exhibit Potent Inhibitory Activity against Muscular Nicotinic Acetylcholine Receptors Mar Drugs 19:705

Internal links

Nucleic acids
Structure

External links

UniProtKB/Swiss-Prot	P01521
Ncbi	P01521

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