M-Conotoxin RIIIK, Structural and Functional Novelty in a K+ Channel Antagonist
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- 作者：Ahmed Al-Sabi ; Dirk Lennartz ; Michael Ferber ; Jozsef Gulyas ; Jean E. F. Rivier ; Baldomero M. Olivera ; Teresa Carlomagno ; and Heinrich Terlau
- 刊名：Biochemistry
- 出版年：2004
- 出版时间：July 13, 2004
- 年：2004
- 卷：43
- 期：27
- 页码：8625 - 8635
- 全文大小：580K
- 年卷期：v.43,no.27(July 13, 2004)
- ISSN：1520-4995
文摘
Venomous organisms have evolved a variety of structurally diverse peptide neurotoxins thattarget ion channels. Despite the lack of any obvious structural homology, unrelated toxins that interactwith voltage-activated K+ channels share a dyad motif composed of a lysine and a hydrophobic aminoacid residue, usually a phenylalanine or a tyrosine. 
fchars/kappa.gif" BORDER=0 >M-Conotoxin RIIIK (fchars/kappa.gif" BORDER=0 >M-RIIIK), recently characterizedfrom the cone snail Conus radiatus, blocks Shaker and TSha1 K+ channels. The functional and structuralstudy presented here reveals that fchars/kappa.gif" BORDER=0 >M-conotoxin RIIIK blocks voltage-activated K+ channels with a novelpharmacophore that does not comprise a dyad motif. Despite the quite different amino acid sequence andno overlap in the pharmacological activity, we found that the NMR solution structure of fchars/kappa.gif" BORDER=0 >M-RIIIK in theC-terminal half is highly similar to that of 
f">-conotoxin GIIIA, a specific blocker of the skeletal muscleNa+ channel Nav1.4. Alanine substitutions of all non-cysteine residues indicated that four amino acids offchars/kappa.gif" BORDER=0 >M-RIIIK (Leu1, Arg10, Lys18, and Arg19) are key determinants for interaction with K+ channels.Following the hypothesis that Leu1, the major hydrophobic amino acid determinant for binding, serves asthe hydrophobic partner of a dyad motif, we investigated the effect of several mutations of Leu1 on thebiological function of fchars/kappa.gif" BORDER=0 >M-RIIIK. Surprisingly, both the structural and mutational analysis suggested that,uniquely among well-characterized K+ channel-targeted toxins, fchars/kappa.gif" BORDER=0 >M-RIIIK blocks voltage-gated K+ channelswith a pharmacophore that is not organized around a lysine-hydrophobic amino acid dyad motif.
fchars/kappa.gif" BORDER=0 >M-Conotoxin RIIIK (fchars/kappa.gif" BORDER=0 >M-RIIIK), recently characterizedfrom the cone snail Conus radiatus, blocks Shaker and TSha1 K+ channels. The functional and structuralstudy presented here reveals that fchars/kappa.gif" BORDER=0 >M-conotoxin RIIIK blocks voltage-activated K+ channels with a novelpharmacophore that does not comprise a dyad motif. Despite the quite different amino acid sequence andno overlap in the pharmacological activity, we found that the NMR solution structure of fchars/kappa.gif" BORDER=0 >M-RIIIK in theC-terminal half is highly similar to that of f">-conotoxin GIIIA, a specific blocker of the skeletal muscleNa+ channel Nav1.4. Alanine substitutions of all non-cysteine residues indicated that four amino acids offchars/kappa.gif" BORDER=0 >M-RIIIK (Leu1, Arg10, Lys18, and Arg19) are key determinants for interaction with K+ channels.Following the hypothesis that Leu1, the major hydrophobic amino acid determinant for binding, serves asthe hydrophobic partner of a dyad motif, we investigated the effect of several mutations of Leu1 on thebiological function of fchars/kappa.gif" BORDER=0 >M-RIIIK. Surprisingly, both the structural and mutational analysis suggested that,uniquely among well-characterized K+ channel-targeted toxins, fchars/kappa.gif" BORDER=0 >M-RIIIK blocks voltage-gated K+ channelswith a pharmacophore that is not organized around a lysine-hydrophobic amino acid dyad motif.