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 ∼100-fold enhanced potency at hα7 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 ¼ 39.1 ± 5.97 nM) showed anti-proliferation effect on A549 cells.

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

Sequence
GCCSDPRCAWRC(nh2)
Modified residues
positionsymbolname
13nh2C-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

TargetOrganismIC50nhillAgonistRef
α1β1δεH. sapiens>10uM50nM AchEllison,M. et al. (2004)
α1β1γδM. musculus51uM500nM AchJohnson,D.S. et al. (1995)
α2β2H. sapiens>10uM100uM AchEllison,M. et al. (2004)
R. norvegicus>5uM300uM AchJohnson,D.S. et al. (1995)
α2β4H. sapiens>10uM100uM AchEllison,M. et al. (2004)
R. norvegicus>5uM300uM AchJohnson,D.S. et al. (1995)
α3β2H. sapiens40.8nM0.9100uM AchEllison,M. et al. (2004)
R. norvegicus>5uM300uM AchJohnson,D.S. et al. (1995)
α3β4H. sapiens3.39uM1.32100uM AchEllison,M. et al. (2004)
R. norvegicus>300uM300nM epibatidineArmishaw,C. et al. (2009)
>5uM300uM AchJohnson,D.S. et al. (1995)
α4β2H. sapiens>10uM100uM AchEllison,M. et al. (2004)
R. norvegicus>5uM300uM AchJohnson,D.S. et al. (1995)
α4β4H. sapiens>10uM100uM AchEllison,M. et al. (2004)
R. norvegicus>5uM300uM AchJohnson,D.S. et al. (1995)
α7H. sapiens2.6uM30uM AchArmishaw,C. et al. (2009)
595nM1.15200uM AchEllison,M. et al. (2004)
130nM+/-300.98500uM AchRogers,J.P. et al. (2000)
497 nM+/-32100 μM AchTabassum et al. (2017)
440 uM+/-30100 μM AchWan et al. (2015)
0.39 uM[0.32-0.48]Dekan,Z. et al. (2011)
R. norvegicus1.04uM+/-0.1250uM AchUtkin,Y.N. et al. (1999)
69nM+/-150.8200uM AchArmishaw,C.J. et al. (2006)
220nM500uM AchJohnson,D.S. et al. (1995)
191 nM0.879 200uM AchEllison,M.A. and McIntosh,J.M. and Olivera,B.M. (2003)
α9R. norvegicus1.8uM100uM AchJohnson,D.S. et al. (1995)

Kd: Nicotinic acetylcholine receptors

TargetOrganismKdRef
α7H. sapiens45.4 uM+/-28.8Wan et al. (2015)

Ki: Nicotinic acetylcholine receptors

TargetOrganismKiCompetitorAgonistRef
α1β1δεH. sapiens119uM+/-43.75nM 125 I-BgtxQuiram,P.A. and Sine,S.M. (1998)
α3β4R. norvegicus>100uM25 pM 3H-epibatidine5mM S-nicotineArmishaw,C. et al. (2009)
>100uM25 pM 3H-epibatidine5mM (S)-nicotineArmishaw,C. et al. (2009)
α7H. sapiens2.45uM+/-0.13.75nM 125 I-BgtxQuiram,P.A. and Sine,S.M. (1998)
α7-5HT3 chimaeraG. gallus4.0uM+/-0.35nM I-BgtxServent,D. et al. (1998)
H. sapiens2.38uM+/-0.053.75nM 125 I-BgtxQuiram,P.A. and Sine,S.M. (1998)
R. norvegicus1.2uM0.5nM 3H-methylcaconitine5mM S-nicotineArmishaw,C. et al. (2009)

Percentage inhibition: Nicotinic acetylcholine receptors

TargetOrganism% inhibitionConcentrationRef
α7H. sapiens83+/-21 uMHoggard 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] deamidatedGCCSDKRCAWRC
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 deamidatedGCCSDPRCAWRC
Imi1G(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

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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