ID CA12_CONMA Reviewed; 68 AA. AC P56636; DT 15-DEC-1998, integrated into UniProtKB/Swiss-Prot. DT 05-SEP-2006, sequence version 3. DT 23-FEB-2022, entry version 106. DE RecName: Full=Alpha-conotoxin MII {ECO:0000303|PubMed:8631783}; DE Short=Alpha-Ctx MII {ECO:0000303|PubMed:9398298}; DE Short=Alpha-MII {ECO:0000303|PubMed:14701840}; DE Flags: Precursor; OS Conus magus (Magical cone). OC Eukaryota; Metazoa; Spiralia; Lophotrochozoa; Mollusca; Gastropoda; OC Caenogastropoda; Neogastropoda; Conoidea; Conidae; Conus; Pionoconus. OX NCBI_TaxID=6492; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Venom duct; RX PubMed=14701840; DOI=10.1074/jbc.m309654200; RA Santos A.D., McIntosh J.M., Hillyard D.R., Cruz L.J., Olivera B.M.; RT "The A-superfamily of conotoxins: structural and functional divergence."; RL J. Biol. Chem. 279:17596-17606(2004). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 28-68. RC TISSUE=Hepatopancreas; RX PubMed=12114524; DOI=10.1074/jbc.m205102200; RA McIntosh J.M., Dowell C., Watkins M., Garrett J.E., Yoshikami D., RA Olivera B.M.; RT "Alpha-conotoxin GIC from Conus geographus, a novel peptide antagonist of RT nicotinic acetylcholine receptors."; RL J. Biol. Chem. 277:33610-33615(2002). RN [3] RP PROTEIN SEQUENCE OF 49-64, FUNCTION, SYNTHESIS OF 49-64, AMIDATION AT RP CYS-64, DISULFIDE BONDS, MASS SPECTROMETRY, AND SUBCELLULAR LOCATION. RC TISSUE=Venom; RX PubMed=8631783; DOI=10.1074/jbc.271.13.7522; RA Cartier G.E., Yoshikami D., Gray W.R., Luo S., Olivera B.M., McIntosh J.M.; RT "A new alpha-conotoxin which targets alpha3beta2 nicotinic acetylcholine RT receptors."; RL J. Biol. Chem. 271:7522-7528(1996). RN [4] RP FUNCTION ON ALPHA-6 ACHR. RX PubMed=11044728; DOI=10.1016/s0028-3908(00)00144-1; RA Kuryatov A., Olale F., Cooper J., Choi C., Lindstrom J.; RT "Human alpha6 AChR subtypes: subunit composition, assembly, and RT pharmacological responses."; RL Neuropharmacology 39:2570-2590(2000). RN [5] RP FUNCTION, AND MUTAGENESIS OF HIS-57 AND LEU-63. RX PubMed=15044624; DOI=10.1124/mol.65.4.944; RA McIntosh J.M., Azam L., Staheli S., Dowell C., Lindstrom J.M., Kuryatov A., RA Garrett J.E., Marks M.J., Whiteaker P.; RT "Analogs of alpha-conotoxin MII are selective for alpha6-containing RT nicotinic acetylcholine receptors."; RL Mol. Pharmacol. 65:944-952(2004). RN [6] RP FUNCTION ON ALPHA-3-3 AND ALPHA-4-BETA-2 NACHR. RX PubMed=15929983; DOI=10.1074/jbc.m504229200; RA Dutertre S., Nicke A., Lewis R.J.; RT "Beta2 subunit contribution to 4/7 alpha-conotoxin binding to the nicotinic RT acetylcholine receptor."; RL J. Biol. Chem. 280:30460-30468(2005). RN [7] RP FUNCTION ON ALPHA-3-BETA-2 NACHR. RX PubMed=16964981; DOI=10.1021/bi0611715; RA Shiembob D.L., Roberts R.L., Luetje C.W., McIntosh J.M.; RT "Determinants of alpha-conotoxin BuIA selectivity on the nicotinic RT acetylcholine receptor beta subunit."; RL Biochemistry 45:11200-11207(2006). RN [8] RP FUNCTION, MUTAGENESIS OF GLY-49; SER-52; ASN-53; PRO-54; VAL-55; HIS-57; RP LEU-58; GLU-59; HIS-60; SER-61; ASN-62 AND LEU-63, AND SYNTHESIS OF 49-64. RX PubMed=15005608; DOI=10.1021/bi036180h; RA Everhart D., Cartier G.E., Malhotra A., Gomes A.V., McIntosh J.M., RA Luetje C.W.; RT "Determinants of potency on alpha-conotoxin MII, a peptide antagonist of RT neuronal nicotinic receptors."; RL Biochemistry 43:2732-2737(2004). RN [9] RP FUNCTION. RX PubMed=20145249; DOI=10.1074/jbc.m109.079012; RA Luo S., Akondi K.B., Zhangsun D., Wu Y., Zhu X., Hu Y., Christensen S., RA Dowell C., Daly N.L., Craik D.J., Wang C.I., Lewis R.J., Alewood P.F., RA Michael McIntosh J.; RT "Atypical alpha-conotoxin LtIA from Conus litteratus targets a novel RT microsite of the alpha3beta2 nicotinic receptor."; RL J. Biol. Chem. 285:12355-12366(2010). RN [10] RP FUNCTION. RX PubMed=25466886; DOI=10.1096/fj.14-262733; RA Heghinian M.D., Mejia M., Adams D.J., Godenschwege T.A., Mari F.; RT "Inhibition of cholinergic pathways in Drosophila melanogaster by alpha- RT conotoxins."; RL FASEB J. 29:1011-1018(2015). RN [11] RP FUNCTION. RX PubMed=32272633; DOI=10.3390/md18040193; RA Osipov A.V., Terpinskaya T.I., Yanchanka T., Balashevich T., Zhmak M.N., RA Tsetlin V.I., Utkin Y.N.; RT "Alpha-conotoxins enhance both the in vivo suppression of Ehrlich carcinoma RT growth and in vitro reduction in cell viability elicited by cyclooxygenase RT and lipoxygenase inhibitors."; RL Mar. Drugs 18:1-11(2020). RN [12] RP FUNCTION. RX PubMed=33523678; DOI=10.1021/acs.jmedchem.0c01973; RA Hone A.J., Kaas Q., Kearns I., Hararah F., Gajewiak J., Christensen S., RA Craik D.J., McIntosh J.M.; RT "Computational and functional mapping of human and rat alpha6beta4 RT nicotinic acetylcholine receptors reveals species-specific ligand-binding RT motifs."; RL J. Med. Chem. 64:1685-1700(2021). RN [13] RP STRUCTURE BY NMR OF 49-64, DISULFIDE BONDS, AND SYNTHESIS OF 49-64. RX PubMed=9398298; DOI=10.1021/bi971443r; RA Shon K.-J., Koerber S.C., Rivier J.E., Olivera B.M., McIntosh J.M.; RT "Three-dimensional solution structure of alpha-conotoxin MII, an RT alpha3beta2 neuronal nicotinic acetylcholine receptor-targeted ligand."; RL Biochemistry 36:15693-15700(1997). RN [14] RP STRUCTURE BY NMR OF 49-64, AMIDATION AT CYS-64, DISULFIDE BONDS, AND RP SYNTHESIS OF 49-64. RX PubMed=9843366; DOI=10.1021/bi981535w; RA Hill J.M., Oomen C.J., Miranda L.P., Bingham J.-P., Alewood P.F., RA Craik D.J.; RT "Three-dimensional solution structure of alpha-conotoxin MII by NMR RT spectroscopy: effects of solution environment on helicity."; RL Biochemistry 37:15621-15630(1998). RN [15] RP STRUCTURE BY NMR OF 49-64, CYCLIZATION, DISULFIDE BONDS, AND SYNTHESIS OF RP 49-64. RX PubMed=16162671; DOI=10.1073/pnas.0504613102; RA Clark R.J., Fischer H., Dempster L., Daly N.L., Rosengren K.J., Nevin S.T., RA Meunier F.A., Adams D.J., Craik D.J.; RT "Engineering stable peptide toxins by means of backbone cyclization: RT stabilization of the alpha-conotoxin MII."; RL Proc. Natl. Acad. Sci. U.S.A. 102:13767-13772(2005). CC -!- FUNCTION: Alpha-conotoxins bind to the nicotinic acetylcholine CC receptors (nAChR) and inhibit them. This toxin blocks neuronal CC mammalian nAChRs (alpha-6/alpha-3-beta-2-beta-3 (0.39 nM) > alpha-3- CC beta-2/CHRNA3-CHRNB2 > alpha-3-beta-4/CHRNA3-CHRNB4 = alpha-4-beta- CC 2/CHRNA4-CHRNB2) (PubMed:15005608, PubMed:20145249). Also exhibits CC inhibition of D.melanogaster alpha-7/CHRNA7 nAChRs (PubMed:25466886). CC In addition, inhibits alpha-6/alpha-3-beta-4 (CHRNA6/CHRNA3-CHRNB4) CC nAChR with a higher potency on human (IC(50)=1.49 nM) than on rat CC receptors (IC(50)=31.5 nM) (PubMed:33523678). Its binding to alpha-3- CC beta-2/CHRNA3-CHRNB2 nAChR is prevented by alpha-conotoxin Lt1a, CC suggesting that the two toxins have overlapping binding sites CC (PubMed:20145249). In addition, both toxins have distinct nAChR binding CC mode (PubMed:20145249). In vivo, inhibits Ehrlich carcinoma growth and CC increase mouse survival (PubMed:32272633). These effects are greatly CC enhanced when the toxin is applied with the non-selective CC cyclooxygenase inhibitor indomethacin (PubMed:32272633). CC {ECO:0000269|PubMed:11044728, ECO:0000269|PubMed:15005608, CC ECO:0000269|PubMed:15044624, ECO:0000269|PubMed:15929983, CC ECO:0000269|PubMed:16964981, ECO:0000269|PubMed:20145249, CC ECO:0000269|PubMed:25466886, ECO:0000269|PubMed:32272633, CC ECO:0000269|PubMed:33523678, ECO:0000269|PubMed:8631783}. CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:8631783}. CC -!- TISSUE SPECIFICITY: Expressed by the venom duct. CC {ECO:0000305|PubMed:8631783}. CC -!- DOMAIN: The cysteine framework is I (CC-C-C). Alpha4/7 pattern. CC {ECO:0000305}. CC -!- MASS SPECTROMETRY: Mass=1710.6; Method=LSI; CC Evidence={ECO:0000269|PubMed:8631783}; CC -!- MISCELLANEOUS: There are currently a number of patents describing the CC use of this peptide in therapeutic applications. CC -!- SIMILARITY: Belongs to the conotoxin A superfamily. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR PIR; A59046; A59046. DR PDB; 1M2C; NMR; -; A=49-64. DR PDB; 1MII; NMR; -; A=49-64. DR PDB; 2AJW; NMR; -; A=49-64. DR PDB; 2AK0; NMR; -; A=49-64. DR PDBsum; 1M2C; -. DR PDBsum; 1MII; -. DR PDBsum; 2AJW; -. DR PDBsum; 2AK0; -. DR SMR; P56636; -. DR TCDB; 8.B.32.1.1; the nicotinic acetylcholine receptor-targeting alpha-conotoxin (a-conotoxin) family. DR ConoServer; 8; MII precursor. DR EvolutionaryTrace; P56636; -. DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell. DR GO; GO:0035792; C:host cell postsynaptic membrane; IEA:UniProtKB-KW. DR GO; GO:0030550; F:acetylcholine receptor inhibitor activity; IEA:UniProtKB-KW. DR GO; GO:0099106; F:ion channel regulator activity; IEA:UniProtKB-KW. DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW. DR InterPro; IPR009958; Conotoxin_a-typ. DR InterPro; IPR018072; Conotoxin_a-typ_CS. DR Pfam; PF07365; Toxin_8; 1. DR PROSITE; PS60014; ALPHA_CONOTOXIN; 1. PE 1: Evidence at protein level; KW 3D-structure; Acetylcholine receptor inhibiting toxin; Amidation; KW Direct protein sequencing; Disulfide bond; Ion channel impairing toxin; KW Neurotoxin; Postsynaptic neurotoxin; Secreted; Signal; Toxin. FT SIGNAL 1..21 FT /evidence="ECO:0000255" FT PROPEP 22..48 FT /evidence="ECO:0000269|PubMed:8631783" FT /id="PRO_0000034881" FT PEPTIDE 49..64 FT /note="Alpha-conotoxin MII" FT /evidence="ECO:0000269|PubMed:8631783" FT /id="PRO_0000034882" FT REGION 52..54 FT /note="Ser-Xaa-Pro motif, crucial for potent interaction FT with nAChR" FT /evidence="ECO:0000305|PubMed:20145249" FT MOD_RES 64 FT /note="Cysteine amide" FT /evidence="ECO:0000269|PubMed:8631783, FT ECO:0000269|PubMed:9843366" FT DISULFID 50..56 FT /evidence="ECO:0000269|PubMed:16162671, FT ECO:0000269|PubMed:9398298, ECO:0000269|PubMed:9843366, FT ECO:0000312|PDB:1M2C, ECO:0000312|PDB:1MII, FT ECO:0000312|PDB:2AJW, ECO:0000312|PDB:2AK0" FT DISULFID 51..64 FT /evidence="ECO:0000269|PubMed:16162671, FT ECO:0000269|PubMed:9398298, ECO:0000269|PubMed:9843366, FT ECO:0000312|PDB:1M2C, ECO:0000312|PDB:1MII, FT ECO:0000312|PDB:2AJW, ECO:0000312|PDB:2AK0" FT MUTAGEN 49 FT /note="G->A: 4.5-fold decrease in ability to inhibit alpha- FT 3-beta-2 nAChR." FT /evidence="ECO:0000269|PubMed:15005608" FT MUTAGEN 52 FT /note="S->A: 4.9-fold decrease in ability to inhibit alpha- FT 3-beta-2 nAChR." FT /evidence="ECO:0000269|PubMed:15005608" FT MUTAGEN 53 FT /note="N->A: >2700-fold decrease in ability to inhibit FT alpha-3-beta-2 nAChR." FT /evidence="ECO:0000269|PubMed:15005608" FT MUTAGEN 54 FT /note="P->A: 700-fold decrease in ability to inhibit alpha- FT 3-beta-2 nAChR." FT /evidence="ECO:0000269|PubMed:15005608" FT MUTAGEN 55 FT /note="V->A: 2.5-fold decrease in ability to inhibit alpha- FT 3-beta-2 nAChR." FT /evidence="ECO:0000269|PubMed:15005608" FT MUTAGEN 57 FT /note="H->A: 2-fold and ~20-fold decrease in ability to FT inhibit alpha-6/alpha-3-beta-2-beta-3 and alpha-3-beta-2, FT respectively. In MII[H9A;L15A]; exhibits preferential loss FT of activity at alpha-3-beta-2 versus alpha-6/alpha-3-beta- FT 2-beta-3 nAChR, making this analog the most selective FT alpha-6 ligand known." FT /evidence="ECO:0000269|PubMed:15005608, FT ECO:0000269|PubMed:15044624" FT MUTAGEN 58 FT /note="L->A: 1.5-fold decrease in ability to inhibit alpha- FT 3-beta-2 nAChR." FT /evidence="ECO:0000269|PubMed:15005608" FT MUTAGEN 59 FT /note="E->A: 4.6-fold decrease in ability to inhibit alpha- FT 3-beta-2 nAChR." FT /evidence="ECO:0000269|PubMed:15005608" FT MUTAGEN 60 FT /note="H->A: About 2700-fold decrease in ability to inhibit FT alpha-3-beta-2 nAChR." FT /evidence="ECO:0000269|PubMed:15005608" FT MUTAGEN 61 FT /note="S->A: 2.3-fold decrease in ability to inhibit alpha- FT 3-beta-2 nAChR." FT /evidence="ECO:0000269|PubMed:15005608" FT MUTAGEN 62 FT /note="N->A: No change in ability to inhibit alpha-3-beta-2 FT nAChR." FT /evidence="ECO:0000269|PubMed:15005608" FT MUTAGEN 63 FT /note="L->A: 2.4-fold and 15-fold decrease in ability to FT inhibit alpha-6/alpha-3-beta-2-beta-3 and alpha-3-beta-2, FT respectively. In MII[H9A;L15A]; exhibits preferential loss FT of activity at alpha-3-beta-2 versus alpha-6/alpha-3-beta- FT 2-beta-3 nAChR, making this analog the most selective FT alpha-6 ligand thus far reported." FT /evidence="ECO:0000269|PubMed:15005608, FT ECO:0000269|PubMed:15044624" FT TURN 50..52 FT /evidence="ECO:0007829|PDB:1MII" FT HELIX 54..59 FT /evidence="ECO:0007829|PDB:1M2C" FT HELIX 61..63 FT /evidence="ECO:0007829|PDB:1M2C" SQ SEQUENCE 68 AA; 7357 MW; FBD9AB40E6F277DF CRC64; MGMRMMFTVF LLVVLATTVV SFPSDRASDG RNAAANDKAS DVITLALKGC CSNPVCHLEH SNLCGRRR //