6YHT

A lid blocking mechanism of a cone snail toxin revealed at the atomic level

Summary for 6YHT

• Entry DOI: 10.2210/pdb6yht/pdb
• Descriptor: Conk-C1, SULFATE ION, CITRIC ACID, ... (4 entities in total)
• Functional Keywords: conkunitzin-3, toxin
• Biological source: Conus cocceus
• Total number of polymer chains: 1
• Total formula weight: 7049.70

Authors

Saikia, C.,Altman-Gueta, H.,Dym, O.,Frolow, F.,Gurevitz, M.,Gordon, D.,Reuveny, E.,Karbat, I. (deposition date: 2020-03-31, release date: 2021-04-14, Last modification date: 2024-11-06)

Primary citation

Saikia, C.,Dym, O.,Altman-Gueta, H.,Gordon, D.,Reuveny, E.,Karbat, I.
A Molecular Lid Mechanism of K + Channel Blocker Action Revealed by a Cone Peptide.
J.Mol.Biol., 433:166957-166957, 2021

PubMed Abstract: 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.

PubMed: 33771569
DOI: 10.1016/j.jmb.2021.166957

Experimental method

X-RAY DIFFRACTION (2.15 Å)