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A molecular lid mechanism of K+ channel blocker action revealed by a cone peptide

Chandamita Saikia, Orly Dym, Hagit Altman-Gueta, Dalia Gordon, Eitan Reuveny, Izhar Karbat
doi: https://doi.org/10.1101/2020.06.15.153577
Chandamita Saikia
1Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel
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Orly Dym
2Structural Proteomic Unit, Weizmann Institute of Science, Rehovot 76100, Israel
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Hagit Altman-Gueta
3Department of Plant Molecular Biology and Ecology, Tel-Aviv University, Tel-Aviv 69978, Israel
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Dalia Gordon
1Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel
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Eitan Reuveny
1Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel
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  • For correspondence: izhar.karbat@weizmann.ac.il e.reuveny@weizmann.ac.il
Izhar Karbat
1Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel
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  • For correspondence: izhar.karbat@weizmann.ac.il e.reuveny@weizmann.ac.il
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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 block of the Drosophila Shaker channel by Conknunitzin-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 in biophysical assays, implying discrete modes of action. We show that while Conknunitzin-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.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Typo in author name corrected.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted June 20, 2020.
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A molecular lid mechanism of K+ channel blocker action revealed by a cone peptide
Chandamita Saikia, Orly Dym, Hagit Altman-Gueta, Dalia Gordon, Eitan Reuveny, Izhar Karbat
bioRxiv 2020.06.15.153577; doi: https://doi.org/10.1101/2020.06.15.153577
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A molecular lid mechanism of K+ channel blocker action revealed by a cone peptide
Chandamita Saikia, Orly Dym, Hagit Altman-Gueta, Dalia Gordon, Eitan Reuveny, Izhar Karbat
bioRxiv 2020.06.15.153577; doi: https://doi.org/10.1101/2020.06.15.153577

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