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TitleA small-molecule activation mechanism that directly opens the KCNQ2 channel.
Journal, issue, pagesNat Chem Biol, Vol. 20, Issue 7, Page 847-856, Year 2024
Publish dateJan 2, 2024
AuthorsShaoying 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 /
PubMed AbstractPharmacological 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 ...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.
External linksNat Chem Biol / PubMed:38167918
MethodsEM (single particle)
Resolution3.0 - 3.4 Å
Structure data

35487

8ijk

EMDB-35487, PDB-8ijk:
human KCNQ2-CaM-Ebio1 complex in the presence of PIP2
Method: EM (single particle) / Resolution: 3.4 Å

38041

8x43

EMDB-38041, PDB-8x43:
human KCNQ2-CaM-Ebio1-S1 complex in the presence of PIP2
Method: EM (single particle) / Resolution: 3.0 Å

Chemicals

ChemComp-7PN:
N-(1,2-dihydroacenaphthylen-5-yl)-4-fluoranyl-benzamide

ChemComp-7Q0:
N-(4-azanyl-1,2-dihydroacenaphthylen-5-yl)-4-fluoranyl-benzamide

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / Potassium voltage-gated channel subfamily KQT member 2 / Ebio1 / Ebio1-S1

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