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Authors
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K.Sato,
Y.Ishida,
K.Wakamatsu,
R.Kato,
H.Honda,
Y.Ohizumi,
H.Nakamura,
M.Ohya,
J.M.Lancelin,
D.Kohda.
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The amino acid sequence of mu-conotoxin GIIIA (otherwise called geographutoxin
I), a peptide having 22 amino acid residues with three disulfide bridges, was
modified by replacing each residue with Ala or Lys to elucidate its active
center for blocking sodium channels of skeletal muscle. NMR and CD spectra were
virtually identical between native and modified toxins, indicating the
similarity of their conformation including disulfide bridges. The inhibitory
effect of these modified peptides on twitch contractions of the rat diaphragm
showed that Arg at the 13th position and the basicity of the molecule are
crucial for the biological action. The segment Lys11-Asp12-Arg13 has been
reported to be flexible (Lancelin, J.-M., Kohda, D., Tate, S., Yanagawa, Y.,
Abe, T., Satake, M., and Inagaki, F. (1991) Biochemistry, in press), and this
may represent a clue for the subtle fit of Arg13 to the specific site of sodium
channels. Since known ligands to sodium channels, such as tetrodotoxin,
anthopleulin-A, etc., contain guanidino groups as a putative binding moiety, Arg
may be a general residue for peptide toxins to interact with the receptor site
on sodium channels.
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