A Molecular Lid Mechanism of K+ Channel Blocker Action Revealed by a Cone Peptide

Many 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. (C) 2021 Elsevier Ltd. All rights reserved.

Automated summary

This study investigates the blocking effects of two highly similar toxins from cone venom on the fruit fly Shaker channel, revealing differences in their binding poses and biophysical assays. Conkunitzin-S1 acts via a pore-collapse mechanism, while Conkunitzin-C3 utilizes a molecular-lid mechanism involving an Arg residue to divert permeant ions.