TY - JOUR
T1 - A small-molecule activation mechanism that directly opens the KCNQ2 channel
AU - Zhang, Shaoying
AU - Ma, Demin
AU - Wang, Kun
AU - Li, Ya
AU - Yang, Zhenni
AU - Li, Xiaoxiao
AU - Li, Junnan
AU - He, Jiangnan
AU - Mei, Lianghe
AU - Ye, Yangliang
AU - Chen, Zongsheng
AU - Shen, Juwen
AU - Hou, Panpan
AU - Guo, Jiangtao
AU - Zhang, Qiansen
AU - Yang, Huaiyu
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.
PY - 2024/7
Y1 - 2024/7
N2 - 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 (+50 mV). 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. (Figure presented.).
AB - 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 (+50 mV). 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. (Figure presented.).
UR - https://www.scopus.com/pages/publications/85181224541
U2 - 10.1038/s41589-023-01515-y
DO - 10.1038/s41589-023-01515-y
M3 - 文章
C2 - 38167918
AN - SCOPUS:85181224541
SN - 1552-4450
VL - 20
SP - 847
EP - 856
JO - Nature Chemical Biology
JF - Nature Chemical Biology
IS - 7
ER -