A physiologically-relevant intermediate state structure of a voltage-gated potassium channel

Efthimios Kyriakis, Daniel Sastre, Jodene Eldstrom, Agnese Roscioni, Sophia Russo, Fariba Ataei, Ying Dou, Magnus Chan, Steven Molinarolo, Luca Maragliano (), Filip Van Petegem () and David Fedida ()
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Efthimios Kyriakis: University of British Columbia
Daniel Sastre: University of British Columbia
Jodene Eldstrom: University of British Columbia
Agnese Roscioni: Via Brecce Bianche
Sophia Russo: University of British Columbia
Fariba Ataei: University of British Columbia
Ying Dou: University of British Columbia
Magnus Chan: University of British Columbia
Steven Molinarolo: University of British Columbia
Luca Maragliano: Via Brecce Bianche
Filip Van Petegem: University of British Columbia
David Fedida: University of British Columbia

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Voltage-gated potassium ion (K+) channels perform critical roles in many physiological processes, while gain- or loss-of-function mutations lead to life-threatening pathologies. Here, we establish the high-resolution structure of a pivotal intermediate state of the Kv7.1 (KCNQ1) channel using cryogenic electron microscopy. The 3.53 Å resolution structure reveals straightened upper S1 and S2 voltage sensor helices, distancing them from the pore filter helix compared to fully activated channels. The outward translation of the S4 voltage sensor is essentially complete in this intermediate state, and the S4-S6 helices and the S4-S5 linker do not change position significantly between intermediate and activated states. The PIP2 ligand can bind in both states. Movement of S1 and S2 helices towards the filter helix from intermediate to activated states may explain smaller components of KCNQ1 voltage sensor fluorescence, differential Rb+/K+ selectivity, and pharmacological responses to activators and inhibitors. Single channel recordings and the location of long QT mutations suggest the potential physiological and disease importance of the intermediate state.

Date: 2025
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-64060-3

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DOI: 10.1038/s41467-025-64060-3

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