1mii
From Proteopedia
SOLUTION STRUCTURE OF ALPHA-CONOTOXIN MII
Structural highlights
FunctionCA12_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 PubMedalpha-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. References
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Categories: Conus magus | Large Structures | Alewood PF | Bingham JP | Craik DJ | Hill JM | Miranda LP | Oomen CJ
