1. A small-molecule activation mechanism that directly opens the KCNQ2 channel
- Author
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Zhang, Shaoying, Ma, Demin, Wang, Kun, Li, Ya, Yang, Zhenni, Li, Xiaoxiao, Li, Junnan, He, Jiangnan, Mei, Lianghe, Ye, Yangliang, Chen, Zongsheng, Shen, Juwen, Hou, Panpan, Guo, Jiangtao, Zhang, Qiansen, and Yang, Huaiyu
- Abstract
Pharmacological activation of voltage-gated ion channels by ligands serves as the basis for therapy and mainly involves a classic gating mechanism that augments the native voltage-dependent open probability. Through structure-based virtual screening, we identified a new scaffold compound, Ebio1, serving as a potent and subtype-selective activator for the voltage-gated potassium channel KCNQ2 and featuring a new activation mechanism. Single-channel patch-clamp, cryogenic-electron microscopy and molecular dynamic simulations, along with chemical derivatives, reveal that Ebio1 engages the KCNQ2 activation by generating an extended channel gate with a larger conductance at the saturating voltage (+50âmV). This mechanism is different from the previously observed activation mechanism of ligands on voltage-gated ion channels. Ebio1 caused S6 helices from residues S303 and F305 to perform a twist-to-open movement, which was sufficient to open the KCNQ2 gate. Overall, our findings provide mechanistic insights into the activation of KCNQ2 channel by Ebio1 and lend support for KCNQ-related drug development.
- Published
- 2024
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