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 12-SEP-2018, entry version 94. 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 (Magus cone) (Magician's cone snail). OC Eukaryota; Metazoa; 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 RT 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 RT of 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., RA McIntosh J.M.; RT "A new alpha-conotoxin which targets alpha3beta2 nicotinic RT acetylcholine 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., RA Kuryatov A., 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 RT nicotinic 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 MUTAGENESIS OF GLY-49; SER-52; ASN-53; PRO-54; VAL-55; HIS-57; LEU-58; RP 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 RT of neuronal nicotinic receptors."; RL Biochemistry 43:2732-2737(2004). RN [9] 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 RT ligand."; RL Biochemistry 36:15693-15700(1997). RN [10] 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 [11] RP STRUCTURE BY NMR OF 49-64, CYCLIZATION, DISULFIDE BONDS, AND SYNTHESIS RP OF 49-64. RX PubMed=16162671; DOI=10.1073/pnas.0504613102; RA Clark R.J., Fischer H., Dempster L., Daly N.L., Rosengren K.J., RA Nevin S.T., 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- CC 3-beta-2 > alpha-3-beta-4 = alpha-4-beta-2). CC {ECO:0000269|PubMed:11044728, ECO:0000269|PubMed:15044624, CC ECO:0000269|PubMed:15929983, ECO:0000269|PubMed:16964981, CC 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; Range=49-64; CC Evidence={ECO:0000269|PubMed:8631783}; CC -!- MISCELLANEOUS: There are currently a number of patents describing CC the 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 ProteinModelPortal; P56636; -. DR SMR; P56636; -. DR ConoServer; 8; MII precursor. DR EvolutionaryTrace; P56636; -. DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell. DR GO; GO:0035792; C:other organism postsynaptic membrane; IEA:UniProtKB-KW. DR GO; GO:0030550; F:acetylcholine receptor inhibitor activity; IEA:InterPro. 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; KW Ion channel impairing toxin; Neurotoxin; Postsynaptic neurotoxin; KW Secreted; Signal; Toxin. FT SIGNAL 1 21 {ECO:0000255}. FT PROPEP 22 48 {ECO:0000269|PubMed:8631783}. FT /FTId=PRO_0000034881. FT PEPTIDE 49 64 Alpha-conotoxin MII. FT {ECO:0000269|PubMed:8631783}. FT /FTId=PRO_0000034882. FT MOD_RES 64 64 Cysteine amide. FT {ECO:0000269|PubMed:8631783, FT ECO:0000269|PubMed:9843366}. FT DISULFID 50 56 {ECO:0000269|PubMed:16162671, FT ECO:0000269|PubMed:9398298, FT ECO:0000269|PubMed:9843366, FT ECO:0000312|PDB:1M2C, FT ECO:0000312|PDB:1MII, FT ECO:0000312|PDB:2AJW, FT ECO:0000312|PDB:2AK0}. FT DISULFID 51 64 {ECO:0000269|PubMed:16162671, FT ECO:0000269|PubMed:9398298, FT ECO:0000269|PubMed:9843366, FT ECO:0000312|PDB:1M2C, FT ECO:0000312|PDB:1MII, FT ECO:0000312|PDB:2AJW, FT ECO:0000312|PDB:2AK0}. FT MUTAGEN 49 49 G->A: 4.5-fold decrease in inhibition of FT alpha-3/beta-2 nAChR. FT {ECO:0000269|PubMed:15005608}. FT MUTAGEN 52 52 S->A: 4.9-fold decrease in inhibition of FT alpha-3/beta-2 nAChR. FT {ECO:0000269|PubMed:15005608}. FT MUTAGEN 53 53 N->A: >2700-fold decrease in inhibition FT of alpha-3/beta-2 nAChR. FT {ECO:0000269|PubMed:15005608}. FT MUTAGEN 54 54 P->A: 700-fold decrease in inhibition of FT alpha-3/beta-2 nAChR. FT {ECO:0000269|PubMed:15005608}. FT MUTAGEN 55 55 V->A: 2.5-fold decrease in inhibition of FT alpha-3/beta-2 nAChR. FT {ECO:0000269|PubMed:15005608}. FT MUTAGEN 57 57 H->A: 2-fold and ~20-fold decrease in FT ability to inhibit alpha-6/alpha-3-beta- FT 2-beta-3 and alpha-3-beta-2, FT respectively. In MII[H9A;L15A]; exhibits FT preferential loss of activity at alpha-3- FT beta-2 versus alpha-6/alpha-3-beta-2- FT beta-3 nAChR, making this analog the most FT selective alpha-6 ligand known. FT {ECO:0000269|PubMed:15005608, FT ECO:0000269|PubMed:15044624}. FT MUTAGEN 58 58 L->A: 1.5-fold decrease in inhibition of FT alpha-3/beta-2 nAChR. FT {ECO:0000269|PubMed:15005608}. FT MUTAGEN 59 59 E->A: 4.6-fold decrease in inhibition of FT alpha-3/beta-2 nAChR. FT {ECO:0000269|PubMed:15005608}. FT MUTAGEN 60 60 H->A: About 2700-fold decrease in FT inhibition of alpha-3/beta-2 nAChR. FT {ECO:0000269|PubMed:15005608}. FT MUTAGEN 61 61 S->A: 2.3-fold decrease in inhibition of FT alpha-3/beta-2 nAChR. FT {ECO:0000269|PubMed:15005608}. FT MUTAGEN 62 62 N->A: No change in inhibition of alpha- FT 3/beta-2 nAChR. FT {ECO:0000269|PubMed:15005608}. FT MUTAGEN 63 63 L->A: 2.4-fold and 15-fold decrease in FT ability to inhibit alpha-6/alpha-3-beta- FT 2-beta-3 and alpha-3-beta-2, FT respectively. In MII[H9A;L15A]; exhibits FT preferential loss of activity at alpha-3- FT beta-2 versus alpha-6/alpha-3-beta-2- FT beta-3 nAChR, making this analog the most FT selective alpha-6 ligand thus far FT reported. {ECO:0000269|PubMed:15005608, FT ECO:0000269|PubMed:15044624}. FT TURN 50 52 {ECO:0000244|PDB:1MII}. FT HELIX 54 59 {ECO:0000244|PDB:1M2C}. FT HELIX 61 63 {ECO:0000244|PDB:1M2C}. SQ SEQUENCE 68 AA; 7357 MW; FBD9AB40E6F277DF CRC64; MGMRMMFTVF LLVVLATTVV SFPSDRASDG RNAAANDKAS DVITLALKGC CSNPVCHLEH SNLCGRRR //