ArticleNature chemical biology2024
A small-molecule activation mechanism that directly opens the KCNQ2 channel.
Article in Nature chemical biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed.
- Molecular Basis for Activation to Inhibition Switching in Kv7.2 Channel Modulators.Angewandte Chemie (International ed. in English) · 2026Article
- Structural basis for the subtype-selective activation of KStructure (London, England : 1993) · 2026Article
- Cannabidiol inhibits both human KActa pharmacologica Sinica · 2026Article
- Structural basis of the neuronal M-current generated by an asymmetric KCNQ2/3 assembly.Cell research · 2026Article
- Hydroxyl-Rich Hyperbranched Polyglycerol Additive for Low-Temperature Aqueous Zinc Batteries: Sustained and Efficient Dehydration and High-Conductivity.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Structural basis for the subtype-selectivity of KNature communications · 2026Article
- Molecular dynamics of the pathogenic KCNQ2 variant G256W reveal mechanisms of channel dysfunction in epileptic encephalopathy.bioRxiv : the preprint server for biology · 2025Article
- Biophysical and structural mechanisms of epilepsy-associated mutations in the S4-S5 Linker of KCNQ2 channels.Channels (Austin, Tex.) · 2025Article
- Accessing sulfonamides via formal SONature chemistry · 2025Article
- The small molecule Ebio3 inactivates the KCNQ2 channel without blocking the pore.Nature chemical biology · 2025Article
- Small molecule inhibits KCNQ channels with a non-blocking mechanism.Nature chemical biology · 2025Article
- Phosphatidylinositol 4,5-bisphosphate activation mechanism of human KCNQ5.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- The conductance of KCNQ2 and its pathogenic variants is determined by individual subunit gating.Science advances · 2025Article
- Evaluation of Small-Molecule Candidates as Modulators of M-Type KInternational journal of molecular sciences · 2025Review
- Ion permeation through a narrow cavity constriction in KCNQ1 channels: Mechanism and implications for pathogenic variants.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Constitutive opening of the Kv7.2 pore activation gate causesProceedings of the National Academy of Sciences of the United States of America · 2024Article
- Stereoselective block of the hERG potassium channel by the Class Ia antiarrhythmic drug disopyramide.Cellular and molecular life sciences : CMLS · 2024Article
- Targeting the ICirculation research · 2024Article
- In Silico Methods for the Discovery of Kv7.2/7.3 Channels Modulators: A Comprehensive Review.Molecules (Basel, Switzerland) · 2024Review
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Authors and funding
16 authors.
Funding
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 (+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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.