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A small-molecule activation mechanism that directly opens the KCNQ2 channel

Nat Chem Biol. 2024-01; 
Shaoying Zhang, Demin Ma, Kun Wang, Ya Li, Zhenni Yang, Xiaoxiao Li, Junnan Li, Jiangnan He, Lianghe Mei, Yangliang Ye, Zongsheng Chen, Juwen Shen, Panpan Hou, Jiangtao Guo, Qiansen Zhang, Huaiyu Yang
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Gene Synthesis … DNAs encoding human KCNQ2 (Homo sapiens NP_004509.2) and CaM (Homo sapiens NP_001734.1) were synthesized by GenScript. To improve the biochemical and thermal … Get A Quote

摘要

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 me... More

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