| Structural highlights
Function
[CXM3A_CONGE] Mu-conotoxins block voltage-gated sodium channels (Nav). This toxin potently blocks Nav1.4/SCN4A. It also moderately blocks rNav1.1/SCN1A, rNav1.2/SCN2A, and mNav1.6/SCN8A. The inhibition is reversible. Induces paralysis in vertebrates.[1] [2] [3]
Publication Abstract from PubMed
A synthetic replacement study of the amino acid residues of mu-conotoxin GIIIA, a peptide blocker for muscle sodium channels, has recently shown that the conformation formed by three disulfide bridges and the molecular basicity, especially the one around the Arg13 residue, are important for blocking activity. In the present study, we determined the three-dimensional structure of an inactive analog, [Ala13]mu-conotoxin GIIIA, and refined that of the native toxin by NMR spectroscopy combined with simulated annealing calculations. The atomic root-mean-square difference of the mutant from the native conotoxin was 0.62 A for the backbone atoms (N, C alpha, C') of all residues except for the two terminal residues. The observation that the replacement of Arg13 by Ala13 does not significantly change the molecular conformation suggests that the loss of activity is not due to the conformational change but to the direct interaction of the essential Arg13 residue with the sodium channel molecules. In the determined structure, important residues for the activity, Arg13, Lys16, Hyp(hydroxyproline)17, and Arg19, are clustered on one side of the molecule, an observation which suggests that this face of the molecule associates with the receptor site of sodium channels. The hydroxyl group of Hyp17 is suggested to interact with the channel site with which the essential hydroxyl groups of tetrodotoxin and saxitoxin interact.
Structure-activity relationships of mu-conotoxin GIIIA: structure determination of active and inactive sodium channel blocker peptides by NMR and simulated annealing calculations.,Wakamatsu K, Kohda D, Hatanaka H, Lancelin JM, Ishida Y, Oya M, Nakamura H, Inagaki F, Sato K Biochemistry. 1992 Dec 22;31(50):12577-84. PMID:1335283[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Cruz LJ, Gray WR, Olivera BM, Zeikus RD, Kerr L, Yoshikami D, Moczydlowski E. Conus geographus toxins that discriminate between neuronal and muscle sodium channels. J Biol Chem. 1985 Aug 5;260(16):9280-8. PMID:2410412
- ↑ Holford M, Zhang MM, Gowd KH, Azam L, Green BR, Watkins M, Ownby JP, Yoshikami D, Bulaj G, Olivera BM. Pruning nature: Biodiversity-derived discovery of novel sodium channel blocking conotoxins from Conus bullatus. Toxicon. 2009 Jan;53(1):90-8. doi: 10.1016/j.toxicon.2008.10.017. Epub 2008 Nov, 20. PMID:18950653 doi:http://dx.doi.org/10.1016/j.toxicon.2008.10.017
- ↑ Wilson MJ, Yoshikami D, Azam L, Gajewiak J, Olivera BM, Bulaj G, Zhang MM. mu-Conotoxins that differentially block sodium channels NaV1.1 through 1.8 identify those responsible for action potentials in sciatic nerve. Proc Natl Acad Sci U S A. 2011 Jun 21;108(25):10302-7. doi:, 10.1073/pnas.1107027108. Epub 2011 Jun 7. PMID:21652775 doi:http://dx.doi.org/10.1073/pnas.1107027108
- ↑ Wakamatsu K, Kohda D, Hatanaka H, Lancelin JM, Ishida Y, Oya M, Nakamura H, Inagaki F, Sato K. Structure-activity relationships of mu-conotoxin GIIIA: structure determination of active and inactive sodium channel blocker peptides by NMR and simulated annealing calculations. Biochemistry. 1992 Dec 22;31(50):12577-84. PMID:1335283
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