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A lid blocking mechanism of a cone snail toxin revealed at the atomic levelA lid blocking mechanism of a cone snail toxin revealed at the atomic level
Structural highlights
FunctionVKTS1_CONST Blocks specifically voltage-activated potassium channels (Kv) of the Shaker family (IC(50)=1.33 nM).[1] Publication Abstract from PubMedMany venomous organisms carry in their arsenal short polypeptides that block K(+) channels in a highly selective manner. These toxins may compete with the permeating ions directly via a "plug" mechanism or indirectly via a "pore-collapse" mechanism. An alternative "lid" mechanism was proposed but remained poorly defined. Here we study the Drosophila Shaker channel block by Conkunitzin-S1 and Conkunitzin-C3, two highly similar toxins derived from cone venom. Despite their similarity, the two peptides exhibited differences in their binding poses and biophysical assays, implying discrete action modes. We show that while Conkunitzin-S1 binds tightly to the channel turret and acts via a "pore-collapse" mechanism, Conkunitzin-C3 does not contact this region. Instead, Conk-C3 uses a non-conserved Arg to divert the permeant ions and trap them in off-axis cryptic sites above the SF, a mechanism we term a "molecular-lid". Our study provides an atomic description of the "lid" K(+) blocking mode and offers valuable insights for the design of therapeutics based on venom peptides. A Molecular Lid Mechanism of K(+) Channel Blocker Action Revealed by a Cone Peptide.,Saikia C, Dym O, Altman-Gueta H, Gordon D, Reuveny E, Karbat I J Mol Biol. 2021 Aug 20;433(17):166957. doi: 10.1016/j.jmb.2021.166957. Epub 2021, Mar 24. PMID:33771569[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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