KappaM-conotoxin RIIIK, structural and functional novelty in a K+ channel antagonist

Biochemistry
Ahmed Al-SabiHeinrich Terlau

Abstract

Venomous organisms have evolved a variety of structurally diverse peptide neurotoxins that target ion channels. Despite the lack of any obvious structural homology, unrelated toxins that interact with voltage-activated K(+) channels share a dyad motif composed of a lysine and a hydrophobic amino acid residue, usually a phenylalanine or a tyrosine. kappaM-Conotoxin RIIIK (kappaM-RIIIK), recently characterized from the cone snail Conus radiatus, blocks Shaker and TSha1 K(+) channels. The functional and structural study presented here reveals that kappaM-conotoxin RIIIK blocks voltage-activated K(+) channels with a novel pharmacophore that does not comprise a dyad motif. Despite the quite different amino acid sequence and no overlap in the pharmacological activity, we found that the NMR solution structure of kappaM-RIIIK in the C-terminal half is highly similar to that of mu-conotoxin GIIIA, a specific blocker of the skeletal muscle Na(+) channel Na(v)1.4. Alanine substitutions of all non-cysteine residues indicated that four amino acids of kappaM-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 bindin...Continue Reading

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Citations

Aug 26, 2009·Cellular and Molecular Life Sciences : CMLS·Reed B Jacob, Owen M McDougal
Mar 15, 2008·Applied Microbiology and Biotechnology·Stefan Becker, Heinrich Terlau
Apr 30, 2010·Chemical Communications : Chem Comm·Jia XuWeihong Du
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Jun 27, 2019·Marine Drugs·Harry Morales DuqueOctávio Luiz Franco
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Aug 23, 2020·Marine Drugs·Estuardo López-VeraJoanna Gajewiak
Mar 28, 2021·Journal of Molecular Biology·Chandamita SaikiaIzhar Karbat

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