A small-molecule activation mechanism that directly opens the KCNQ2 channel.
Nat Chem Biol
; 20(7): 847-856, 2024 Jul.
Article
em En
| MEDLINE
| ID: mdl-38167918
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ativação do Canal Iônico
/
Canal de Potássio KCNQ2
/
Simulação de Dinâmica Molecular
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Nat Chem Biol
/
Nat. chem. biol
/
Nature chemical biology
Assunto da revista:
BIOLOGIA
/
QUIMICA
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China