1mii

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SOLUTION STRUCTURE OF ALPHA-CONOTOXIN MII

Structural highlights

1mii is a 1 chain structure with sequence from Conus magus. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Solution NMR
Ligands:NH2
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CA12_CONMA Alpha-conotoxins bind to the nicotinic acetylcholine receptors (nAChR) and inhibit them. This toxin blocks neuronal mammalian nAChRs (alpha-6/alpha-3-beta-2-beta-3 (0.39 nM) > alpha-3-beta-2/CHRNA3-CHRNB2 > alpha-3-beta-4/CHRNA3-CHRNB4 = alpha-4-beta-2/CHRNA4-CHRNB2) (PubMed:15005608, PubMed:20145249). Also exhibits inhibition of D.melanogaster alpha-7/CHRNA7 nAChRs (PubMed:25466886). In addition, inhibits alpha-6/alpha-3-beta-4 (CHRNA6/CHRNA3-CHRNB4) nAChR with a higher potency on human (IC(50)=1.49 nM) than on rat receptors (IC(50)=31.5 nM) (PubMed:33523678). Its binding to alpha-3-beta-2/CHRNA3-CHRNB2 nAChR is prevented by alpha-conotoxin Lt1a, suggesting that the two toxins have overlapping binding sites (PubMed:20145249). In addition, both toxins have distinct nAChR binding mode (PubMed:20145249). In vivo, inhibits Ehrlich carcinoma growth and increase mouse survival (PubMed:32272633). These effects are greatly enhanced when the toxin is applied with the non-selective cyclooxygenase inhibitor indomethacin (PubMed:32272633).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10]

Publication Abstract from PubMed

alpha-Conotoxin MII, a 16-residue polypeptide from the venom of the piscivorous cone snail Conus magus, is a potent and highly specific blocker of mammalian neuronal nicotinic acetylcholine receptors composed of alpha3 beta2 subunits. The role of this receptor type in the modulation of neurotransmitter release and its relevance to the problems of addiction and psychosis emphasize the importance of a structural understanding of the mode of interaction of MII with the alpha3 beta2 interface. Here we describe the three-dimensional solution structure of MII determined using 2D 1H NMR spectroscopy. Structural restraints consisting of 376 interproton distances inferred from NOEs and 12 dihedral restraints derived from spin-spin coupling constants were used as input for simulated annealing calculations and energy minimization in the program X-PLOR. The final set of 20 structures is exceptionally well-defined with mean pairwise rms differences over the whole molecule of 0.07 A for the backbone atoms and 0.34 A for all heavy atoms. MII adopts a compact structure incorporating a central segment of alpha-helix and beta-turns at the N- and C-termini. The molecule is stabilized by two disulfide bonds, which provide cross-links between the N-terminus and both the middle and C-terminus of the structure. The susceptibility of the structure to conformational change was examined using several different solvent conditions. While the global fold of MII remains the same, the structure is stabilized in a more hydrophobic environment provided by the addition of acetonitrile or trifluoroethanol to the aqueous solution. The distribution of amino acid side chains in MII creates distinct hydrophobic and polar patches on its surface that may be important for the specific interaction with the alpha3beta2 neuronal nAChR. A comparison of the structure of MII with other neuronal-specific alpha-conotoxins provides insights into their mode of interaction with these receptors.

Three-dimensional solution structure of alpha-conotoxin MII by NMR spectroscopy: effects of solution environment on helicity.,Hill JM, Oomen CJ, Miranda LP, Bingham JP, Alewood PF, Craik DJ Biochemistry. 1998 Nov 10;37(45):15621-30. PMID:9843366[11]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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References

  1. ↑ Kuryatov A, Olale F, Cooper J, Choi C, Lindstrom J. Human alpha6 AChR subtypes: subunit composition, assembly, and pharmacological responses. Neuropharmacology. 2000 Oct;39(13):2570-90. PMID:11044728
  2. ↑ Everhart D, Cartier GE, Malhotra A, Gomes AV, McIntosh JM, Luetje CW. Determinants of potency on alpha-conotoxin MII, a peptide antagonist of neuronal nicotinic receptors. Biochemistry. 2004 Mar 16;43(10):2732-7. PMID:15005608 doi:10.1021/bi036180h
  3. ↑ McIntosh JM, Azam L, Staheli S, Dowell C, Lindstrom JM, Kuryatov A, Garrett JE, Marks MJ, Whiteaker P. Analogs of alpha-conotoxin MII are selective for alpha6-containing nicotinic acetylcholine receptors. Mol Pharmacol. 2004 Apr;65(4):944-52. PMID:15044624 doi:10.1124/mol.65.4.944
  4. ↑ Dutertre S, Nicke A, Lewis RJ. Beta2 subunit contribution to 4/7 alpha-conotoxin binding to the nicotinic acetylcholine receptor. J Biol Chem. 2005 Aug 26;280(34):30460-8. Epub 2005 Jun 1. PMID:15929983 doi:http://dx.doi.org/10.1074/jbc.M504229200
  5. ↑ Shiembob DL, Roberts RL, Luetje CW, McIntosh JM. Determinants of alpha-conotoxin BuIA selectivity on the nicotinic acetylcholine receptor beta subunit. Biochemistry. 2006 Sep 19;45(37):11200-7. PMID:16964981 doi:10.1021/bi0611715
  6. ↑ Luo S, Akondi KB, Zhangsun D, Wu Y, Zhu X, Hu Y, Christensen S, Dowell C, Daly NL, Craik DJ, Wang CI, Lewis RJ, Alewood PF, Michael McIntosh J. Atypical alpha-conotoxin LtIA from Conus litteratus targets a novel microsite of the alpha3beta2 nicotinic receptor. J Biol Chem. 2010 Apr 16;285(16):12355-66. PMID:20145249 doi:10.1074/jbc.M109.079012
  7. ↑ Heghinian MD, Mejia M, Adams DJ, Godenschwege TA, Marí F. Inhibition of cholinergic pathways in Drosophila melanogaster by α-conotoxins. FASEB J. 2015 Mar;29(3):1011-8. PMID:25466886 doi:10.1096/fj.14-262733
  8. ↑ Osipov AV, Terpinskaya TI, Yanchanka T, Balashevich T, Zhmak MN, Tsetlin VI, Utkin YN. α-Conotoxins Enhance both the In Vivo Suppression of Ehrlich carcinoma Growth and In Vitro Reduction in Cell Viability Elicited by Cyclooxygenase and Lipoxygenase Inhibitors. Mar Drugs. 2020 Apr 7;18(4):193. PMID:32272633 doi:10.3390/md18040193
  9. ↑ Hone AJ, Kaas Q, Kearns I, Hararah F, Gajewiak J, Christensen S, Craik DJ, McIntosh JM. Computational and Functional Mapping of Human and Rat α6β4 Nicotinic Acetylcholine Receptors Reveals Species-Specific Ligand-Binding Motifs. J Med Chem. 2021 Feb 11;64(3):1685-1700. PMID:33523678 doi:10.1021/acs.jmedchem.0c01973
  10. ↑ Cartier GE, Yoshikami D, Gray WR, Luo S, Olivera BM, McIntosh JM. A new alpha-conotoxin which targets alpha3beta2 nicotinic acetylcholine receptors. J Biol Chem. 1996 Mar 29;271(13):7522-8. PMID:8631783
  11. ↑ Hill JM, Oomen CJ, Miranda LP, Bingham JP, Alewood PF, Craik DJ. Three-dimensional solution structure of alpha-conotoxin MII by NMR spectroscopy: effects of solution environment on helicity. Biochemistry. 1998 Nov 10;37(45):15621-30. PMID:9843366 doi:http://dx.doi.org/10.1021/bi981535w

Contents


PDB ID 1mii

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