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.
| Original language | English |
|---|---|
| Article number | 166957 |
| Number of pages | 16 |
| Journal | Journal of Molecular Biology |
| Volume | 433 |
| Issue number | 17 |
| Early online date | 24 Mar 2021 |
| DOIs | |
| Publication status | Published - 20 Aug 2021 |
Funding
This study was supported, in part, by The Israeli Science Foundation Grant Number 1248/15, the Minerva Foundation and the Willner Family Fund (to E.R.). E.R. is the incumbent of the Charles H. Hollenberg Professorial Chair. We would like to acknowledge Prof. Felix Frolow and Prof. Miki Gurevitz for their invaluable assistance in crystallization and initial data collection of Conk-C1 and Conk-C3, and Dr. Gili Ben-Nisan for her assistance with the mass-spectrometry analyses.