ImI (P00010) Protein Card

General Information

Name	ImI
Organism	Conus imperialis
Organism region	Indo-Pacific
Organism diet	vermivorous
Protein Type	Wild type
Protein precursor	ImI precursor (93)
Notes	Wan et al. (2015) reported that di- and tetravalent dendrimers of ImI with polyethylene glycol spacers showed about 100-fold enhanced potency at α7 nAChRs (IC50 = 4.3 ± 0.9, and 6.7 ± 0.8 nM for di and treta, respectively) compared to native ImI (IC50 = 440 nM). Mei et al. (2018) reported that ImI-PM-DTX (IC50 = 39.1 ± 5.97 nM) showed anti-proliferation effect on A549 cells. By comparing the structures of α-conotoxins in complex with Ac-AChBP and by modelling α-conotoxins in complex with nAChRs, Lin et al. (2016) indicated that (i) Arg-7 is responsible for the selectivity for the Ac-AChBP principal site; (ii) Ser-4 is important for interaction with the Ac-AChBP complementary side; (iii) Trp-10 is responsible for the selectivity for the Ac-AChBP complementary side.

Classification

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

Sequence

GCCSDPRCAWRC(nh2)

Modified residues

position	symbol	name
13	nh2	C-term amidation

Sequence evidence

protein level

Average Mass

1351.55

Monoisotopic Mass

1350.48

Isoelectric Point

10.99

Extinction Coefficient [280nm]

5500.00

Activity

IC50: Nicotinic acetylcholine receptors

Target	Organism	IC50		n_hill	Agonist	Ref
α1β1δε	H. sapiens	>10uM			50nM Ach	Ellison,M. et al. (2004)
α1β1γδ	M. musculus	51uM			500nM Ach	Johnson,D.S. et al. (1995)
α2β2	H. sapiens	>10uM			100uM Ach	Ellison,M. et al. (2004)
	R. norvegicus	>5uM			300uM Ach	Johnson,D.S. et al. (1995)
α2β4	H. sapiens	>10uM			100uM Ach	Ellison,M. et al. (2004)
	R. norvegicus	>5uM			300uM Ach	Johnson,D.S. et al. (1995)
α3β2	H. sapiens	40.8nM		0.9	100uM Ach	Ellison,M. et al. (2004)
	R. norvegicus	>5uM			300uM Ach	Johnson,D.S. et al. (1995)
α3β4	H. sapiens	3.39uM		1.32	100uM Ach	Ellison,M. et al. (2004)
	R. norvegicus	>300uM			300nM epibatidine	Armishaw,C. et al. (2009)
		>5uM			300uM Ach	Johnson,D.S. et al. (1995)
α4β2	H. sapiens	>10uM			100uM Ach	Ellison,M. et al. (2004)
	R. norvegicus	>5uM			300uM Ach	Johnson,D.S. et al. (1995)
α4β4	H. sapiens	>10uM			100uM Ach	Ellison,M. et al. (2004)
	R. norvegicus	>5uM			300uM Ach	Johnson,D.S. et al. (1995)
α7	H. sapiens	2.6uM			30uM Ach	Armishaw,C. et al. (2009)
		595nM		1.15	200uM Ach	Ellison,M. et al. (2004)
		130nM	+/-30	0.98	500uM Ach	Rogers,J.P. et al. (2000)
		497 nM	+/-32		100 μM Ach	Tabassum et al. (2017)
		440 uM	+/-30		100 μM Ach	Wan et al. (2015)
		0.39 uM	[0.32-0.48]			Dekan,Z. et al. (2011)
	R. norvegicus	1.04uM	+/-0.12		50uM Ach	Utkin,Y.N. et al. (1999)
		69nM	+/-15	0.8	200uM Ach	Armishaw,C.J. et al. (2006)
		220nM			500uM Ach	Johnson,D.S. et al. (1995)
		191 nM		0.879	200uM Ach	Ellison,M.A. and McIntosh,J.M. and Olivera,B.M. (2003)
α9	R. norvegicus	1.8uM			100uM Ach	Johnson,D.S. et al. (1995)

Kd: Nicotinic acetylcholine receptors

Target	Organism	Kd		Ref
α7	H. sapiens	45.4 uM	+/-28.8	Wan et al. (2015)

Ki: Nicotinic acetylcholine receptors

Target	Organism	Ki		Competitor	Agonist	Ref
α1β1δε	H. sapiens	119uM	+/-4	3.75nM 125 I-Bgtx		Quiram,P.A. and Sine,S.M. (1998)
α3β4	R. norvegicus	>100uM		25 pM 3H-epibatidine	5mM (S)-nicotine	Armishaw,C. et al. (2009)
		>100uM		25 pM 3H-epibatidine	5mM S-nicotine	Armishaw,C. et al. (2009)
α7	H. sapiens	2.45uM	+/-0.1	3.75nM 125 I-Bgtx		Quiram,P.A. and Sine,S.M. (1998)
α7-5HT3 chimaera	G. gallus	4.0uM	+/-0.3	5nM I-Bgtx		Servent,D. et al. (1998)
	H. sapiens	2.38uM	+/-0.05	3.75nM 125 I-Bgtx		Quiram,P.A. and Sine,S.M. (1998)
	R. norvegicus	1.2uM		0.5nM 3H-methylcaconitine	5mM S-nicotine	Armishaw,C. et al. (2009)

Percentage inhibition: Nicotinic acetylcholine receptors

Target	Organism	% inhibition		Concentration	Ref
α7	H. sapiens	83	+/-2	1 uM	Hoggard et al. (2017)

Synthetic variants

Ac-ImI	(Ac)GCCSDPRCAWRC(nh2)
ImI [A9L,W10Y,R11ABA]	GCCSDPRCLY(Abu)C
ImI [A9S]	GCCSDPRCAWRC(nh2)
ImI [C2Agl,C8Agl]	G(Agl)CSDPR(Agl)AWRC(nh2)
ImI [C2H,C8F]	GHCSDPRFAWRC(nh2)
ImI [C2U,C3U,C8U,C12U]	GUUSDPRUAWRU(nh2)
ImI [C2U,C8U]	GUCSDPRUAWRC(nh2)
ImI [C3U,C12U]	GCUSDPRCAWRU(nh2)
ImI [Cys2-8Ctt, Cys3-12Ctt]	G(Ctt_hc)(Ctt_hc)SDPR(Ctt_ser)AWR(Ctt_ser)(nh2)
ImI [Cys2-8Ctt]	G(Ctt_hc)CSDPR(Ctt_ser)AWRC(nh2)
ImI [Cys3-12Ctt]	GC(Ctt_hc)SDPRCAWR(Ctt_ser)(nh2)
ImI [D5A]	GCCSAPRCAWRC(nh2)
ImI [D5E]	GCCSEPRCAWRC(nh2)
ImI [D5K]	GCCSKPRCAWRC(nh2)
ImI [D5N]	GCCSNPRCAWRC(nh2)
ImI [D5R,R7D]	GCCSRPDCAWRC(nh2)
ImI [G1A]	ACCSDPRCAWRC(nh2)
ImI [P60]	GCCSDORCAWRC(nh2)
ImI [P6A(S)Pro]	GCCSD(A(S)Pro)RCAWRC(nh2)
ImI [P6APro]	GCCSD(APro)RCAWRC(nh2)
ImI [P6A]	GCCSDARCAWRC(nh2)
ImI [P6G]	GCCSDGRCAWRC(nh2)
ImI [P6K]	GCCSDKRCAWRC(nh2)
ImI [P6K] deamidated	GCCSDKRCAWRC
ImI [P6S]	GCCSDSRCAWRC(nh2)
ImI [P6V]	GCCSDVRCAWRC(nh2)
ImI [P6benzPro]	GCCSD(benz-Pro)RCAWRC(nh2)
ImI [P6betPro]	GCCSD(bet-Pro)RCAWRC(nh2)
ImI [P6fluo(S)Pro]	GCCSD(F-(S)-Pro)RCAWRC(nh2)
ImI [P6fluoPro]	GCCSD(F-Pro)RCAWRC(nh2)
ImI [P6guaPro]	GCCSD(Gua-Pro)RCAWRC(nh2)
ImI [P6naphPro]	GCCSD(naph-Prot)RCAWRC(nh2)
ImI [P6phi(3S)Pro]	GCCSD(phi3-Pro)RCAWRC(nh2)
ImI [P6phi(5R)Pro]	GCCSD(phi5-Pro)RCAWRC(nh2)
ImI [P6phi(S)Pro]	GCCSD(phi-(S)-Pro)RCAWRC(nh2)
ImI [P6phiPro]	GCCSD(phi-Pro)RCAWRC(nh2)
ImI [R11A]	GCCSDPRCAWAC(nh2)
ImI [R11E]	GCCSDPRCAWEC(nh2)
ImI [R11Q]	GCCSDPRCAWQC(nh2)
ImI [R7A]	GCCSDPACAWRC(nh2)
ImI [R7E]	GCCSDPECAWRC(nh2)
ImI [R7K]	GCCSDPKCAWRC(nh2)
ImI [R7L]	GCCSDPLCAWRC(nh2)
ImI [R7Nle]	GCCSDP(Nle)CAWRC(nh2)
ImI [R7Q]	GCCSDPQCAWRC(nh2)
ImI [S4A]	GCCADPRCAWRC(nh2)
ImI [W10A]	GCCSDPRCAARC(nh2)
ImI [W10F]	GCCSDPRCAFRC(nh2)
ImI [W10T]	GCCSDPRCATRC(nh2)
ImI [W10Y]	GCCSDPRCAYRC(nh2)
ImI deamidated	GCCSDPRCAWRC
Imi1	G(L-Dtn)ASDPRCAWRC(nh2)

References

McIntosh,J.M., Yoshikami,D., Mahe,E., Nielsen,D.B., Rivier,J.E., Gray,W.R. and Olivera,B.M. (1994) A nicotinic acetylcholine receptor ligand of unique specificity, alpha-conotoxin ImI J. Biol. Chem. 269:16733-16739

Servent,D., Lamthanh,H., Antil,S., Bertrand,D., Corringer,P.J., Changeux,J.P. and Menez,A. (1998) Functional Determinants By Which Snake And Cone Snail Toxins Block The Alpha 7 Neuronal Nicotinic Acetylcholine Receptors J.Physiol. Paris 92:107-111

Quiram,P.A. and Sine,S.M. (1998) Identification of residues in the neuronal alpha7 acetylcholine receptor that confer selectivity for conotoxin ImI J. Biol. Chem. 273:11001-11006

Maslennikov,I.V., Shenkarev,Z.O., Zhmak,M.N., Ivanov,V.T., Methfessel,C., Tsetlin,V.I. and Arseniev,A.S. (1999) NMR spatial structure of alpha-conotoxin ImI reveals a common scaffold in snail and snake toxins recognizing neuronal nicotinic acetylcholine receptors FEBS Lett. 444:275-280

Rogers,J.P., Luginbuhl,P., Shen,G.S., McCabe,R.T., Stevens,R.C. and Wemmer,D.E. (1999) NMR solution structure of alpha-conotoxin ImI and comparison to other conotoxins specific for neuronal nicotinic acetylcholine receptors Biochemistry 38:3874-3882

Lamthanh,H., Jegou-Matheron,C., Servent,D., Menez,A. and Lancelin,J.M. (1999) Minimal conformation of the alpha-conotoxin ImI for the alpha7 neuronal nicotinic acetylcholine receptor recognition: correlated CD, NMR and binding studies FEBS Lett. 454:293-298

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

Ellison,M.A., McIntosh,J.M. and Olivera,B.M. (2003) alpha-Conotoxins ImI and ImII: similar alpha 7 nicotinic receptor antagonists act at different sites J. Biol. Chem. 278:757-764

Gehrmann,J., Daly,N.L., Alewood,P.F. and Craik,D.J. (1999) Solution structure of alpha-conotoxin ImI by 1H nuclear magnetic resonance J. Med. Chem. 42:2364-2372

Hansen,S.B., Sulzenbacher,G., Huxford,T., Marchot,P., Taylor,P. and Bourne,Y. (2005) Structures Of Aplysia Achbp Complexes With Nicotinic Agonists And Antagonists Reveal Distinctive Binding Interfaces And Conformations Embo J. 24:3635

Ulens,C., Hogg,R.C., Celie,P.H., Bertrand,D., Tsetlin,V., Smit,A.B. and Sixma,T.K. (2006) Structural determinants of selective alpha-conotoxin binding to a nicotinic acetylcholine receptor homolog AChBP Proc. Natl. Acad. Sci. U.S.A. 103:3615-3620

Armishaw,C.J., Daly,N.L., Nevin,S.T., Adams,D.J., Craik,D.J. and Alewood,P.F. (2006) Alpha-selenoconotoxins, a new class of potent alpha7 neuronal nicotinic receptor antagonists J. Biol. Chem. 281:14136-14143

Ellison,M., Gao,F., Wang,H.L., Sine,S.M. and Olivera,B.M. (2004) Alpha-conotoxins ImI and ImII target distinct regions of the human alpha7 nicotinic acetylcholine receptor and distinguish human nicotinic receptor subtypes. Biochemistry 43:16019-16026

Yu,R., Craik,D.J. and Kaas,Q. (2011) Blockade of neuronal α7-nAChR by α-conotoxin ImI explained by computational scanning and energy calculations. PLoS Comput. Biol. 7

Armishaw,C., Jensen,A.A., Balle,T., Clark,R.J., Harpsøe,K., Skonberg,C., Liljefors,T. and Strømgaard,K. (2009) Rational design of alpha-conotoxin analogues targeting alpha7 nicotinic acetylcholine receptors: improved antagonistic activity by incorporation of proline derivatives. J. Biol. Chem. 284:9498-9512

Armishaw,C.J., Singh,N., Medina-Franco,J.L., Clark,R.J., Scott,K.C., Houghten,R.A. and Jensen,A.A. (2010) A synthetic combinatorial strategy for developing alpha-conotoxin analogs as potent alpha7 nicotinic acetylcholine receptor antagonists. J. Biol. Chem. 285:1809-1821

Utkin,Y.N., Zhmak,M.N., Methfessel,C. and Tsetlin,V.I. (1999) Aromatic substitutions in alpha-conotoxin ImI. Synthesis of iodinated photoactivatable derivative. Toxicon 37:1683-1695

Yu,R., Kaas,Q. and Craik,D.J. (2012) Delineation of the unbinding pathway of α-conotoxin ImI from the α7 nicotinic acetylcholine receptor. J Phys Chem B 116:6097-6105

Xu, X., Liang, J., Zhang, Z., Jiang, T. and Yu, R. (2019) Blockade of Human α7 Nicotinic Acetylcholine Receptor by α-Conotoxin ImI Dendrimer: Insight from Computational Simulations Marine drugs 17:303

Tabassum, N., Tae, H.S., Jia, X., Kaas, Q., Jiang, T., Adams, D.J. and Yu, R. (2017) Role of CysI-CysIII Disulfide Bond on the Structure and Activity of α-Conotoxins at Human Neuronal Nicotinic Acetylcholine Receptors ACS omega 2:4621-4631

Wan, J., Huang, J.X., Vetter, I., Mobli, M., Lawson, J., Tae, H.S., Abraham, N., Paul, B., Cooper, M.A., Adams, D.J. and Lewis, R.J. (2015) α-Conotoxin dendrimers have enhanced potency and selectivity for homomeric nicotinic acetylcholine receptors Journal of the American Chemical Society 137:3209-3212

Mei, D., Zhao, L., Chen, B., Zhang, X., Wang, X., Yu, Z., Ni, X. and Zhang, Q. (2018) α-Conotoxin ImI-modified polymeric micelles as potential nanocarriers for targeted docetaxel delivery to α7-nAChR overexpressed non-small cell lung cancer Drug Delivery 25:493-503

Hoggard, M.F., Rodriguez, A.M., Cano, H., Clark, E., Tae, H.S., Adams, D.J., Godenschwege, T.A. and Marí, F (2017) In vivo and in vitro testing of native α-conotoxins from the injected venom of Conus purpurascens Neuropharmacology 127:253-259

Dekan,Z., Vetter,I., Daly,N.L., Craik,D.J., Lewis,R.J. and Alewood,P.F. (2011) α-Conotoxin ImI incorporating stable cystathionine bridges maintains full potency and identical three-dimensional structure J. Am. Chem. Soc. 133:15866-15869

Gao,B., Peng,C., Lin,B., Chen,Q., Zhang,J. and Shi,Q. (2017) Screening and Validation of Highly-Efficient Insecticidal Conotoxins from a Transcriptome-Based Dataset of Chinese Tubular Cone Snail Toxins (Basel) 9:214

Lin,B., Xiang,S., and Li,M. (2016) Residues Responsible for the Selectivity of α-Conotoxins for Ac-AChBP or nAChRs. Marine drugs 14:173

Internal links

Protein Precursor	ImI precursor (93)
Nucleic acids
Structure	MINIMAL CONFORMATION OF THE ALPHA-CONOTOXIN IMI FOR THE ALPHA7 NEURONAL NICOTINIC ACETYLCHOLINE RECEPTOR RECOGNITION SOLUTION STRUCTURE OF ALPHA-CONOTOXIN IM1 ALPHA-CONOTOXIN IMI NMR SOLUTION STRUCTURE OF ALPHA-CONOTOXIN IM1, 20 STRUCTURES CRYSTAL STRUCTURE OF APLYSIA CALIFORNICA ACHBP IN COMPLEX WITH ALPHA-CONOTOXIN IMI CRYSTAL STRUCTURE OF ACETYLCHOLINE BINDING PROTEIN (ACHBP) FROM APLYSIA CALIFORNICA IN COMPLEX WITH ALPHA-CONOTOXIN IMI

External links

Ncbi

1CNL_A, 1G2G_A, 1IM1_A, 1IMI_A, 2BYP_F, 2C9T_K, 2C9T_M, 2C9T_O, 2C9T_P, 2C9T_Q, 2C9T_R, 2C9T_S, 2C9T_T

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