1tch
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STRUCTURE-ACTIVITY RELATIONSHIPS OF MU-CONOTOXIN GIIIA: STRUCTURE DETERMINATION OF ACTIVE AND INACTIVE SODIUM CHANNEL BLOCKER PEPTIDES BY NMR AND SIMULATED ANNEALING CALCULATIONS
OverviewOverview
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.
About this StructureAbout this Structure
1TCH is a Single protein structure of sequence from [1] with NH2 as ligand. Full crystallographic information is available from OCA.
ReferenceReference
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
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