8IJK

human KCNQ2-CaM-Ebio1 complex in the presence of PIP2

Summary for 8IJK

• Entry DOI: 10.2210/pdb8ijk/pdb
• EMDB information: 35487
• Descriptor: Potassium voltage-gated channel subfamily KQT member 2, Calmodulin-1, N-(1,2-dihydroacenaphthylen-5-yl)-4-fluoranyl-benzamide (3 entities in total)
• Functional Keywords: potassium voltage-gated channel subfamily kqt member 2, ebio1, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 8
• Total formula weight: 363086.70

Authors

Ma, D.,Guo, J. (deposition date: 2023-02-27, release date: 2024-01-17, Last modification date: 2024-07-10)

Primary citation

Zhang, S.,Ma, D.,Wang, K.,Li, Y.,Yang, Z.,Li, X.,Li, J.,He, J.,Mei, L.,Ye, Y.,Chen, Z.,Shen, J.,Hou, P.,Guo, J.,Zhang, Q.,Yang, H.
A small-molecule activation mechanism that directly opens the KCNQ2 channel.
Nat.Chem.Biol., 20:847-856, 2024

PubMed 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.

PubMed: 38167918
DOI: 10.1038/s41589-023-01515-y

Experimental method

ELECTRON MICROSCOPY (3.4 Å)