The 3.53 Å resolution cryo-EM structure of the KCNQ1 intermediate state reveals straightened upper S1 and S2 voltage sensor helices compared to fully activated channels.
The structural elucidation of the KCNQ1 channel intermediate state provides mechanistic insights into channel gating and long QT syndrome mutations, potentially guiding targeted drug development.
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. KCNQ1 (Kv7.1) channels are critical for heart rhythm homeostasis. Here, the authors report the KCNQ1 structure in an intermediate state, revealing unique S1–S2 conformations that illuminate channel gating and may aid targeted drug development.
Kyriakis et al. (Fri,) conducted a other in KCNQ1 channelopathies. xE1R/R2E mutation vs. Wild-type xKCNQ1 was evaluated on Cryo-EM structure of the intermediate state. The 3.53 Å resolution cryo-EM structure of the KCNQ1 intermediate state reveals straightened upper S1 and S2 voltage sensor helices compared to fully activated channels.