7BYL

Cryo-EM structure of human KCNQ4

Summary for 7BYL

• Entry DOI: 10.2210/pdb7byl/pdb
• EMDB information: 30244
• Descriptor: Green fluorescent protein,Potassium voltage-gated channel subfamily KQT member 4, Calmodulin-3, [(2R)-1-octadecanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phospho ryl]oxy-propan-2-yl] (8Z)-icosa-5,8,11,14-tetraenoate, ... (5 entities in total)
• Functional Keywords: kcnq, channel, calmodulin, pip2, membrane protein
• Biological source: Aequorea victoria (Jellyfish); More
• Total number of polymer chains: 8
• Total formula weight: 509066.27

Authors

Shen, H.,Li, T.,Yue, Z. (deposition date: 2020-04-23, release date: 2020-12-02, Last modification date: 2024-03-27)

Primary citation

Li, T.,Wu, K.,Yue, Z.,Wang, Y.,Zhang, F.,Shen, H.
Structural Basis for the Modulation of Human KCNQ4 by Small-Molecule Drugs.
Mol.Cell, 81:25-, 2021

PubMed Abstract: Among the five KCNQ channels, also known as the K7 voltage-gated potassium (K) channels, KCNQ2-KCNQ5 control neuronal excitability. Dysfunctions of KCNQ2-KCNQ5 are associated with neurological disorders such as epilepsy, deafness, and neuropathic pain. Here, we report the cryoelectron microscopy (cryo-EM) structures of human KCNQ4 and its complexes with the opener retigabine or the blocker linopirdine at overall resolutions of 2.5, 3.1, and 3.3 Å, respectively. In all structures, a phosphatidylinositol 4,5-bisphosphate (PIP) molecule inserts its head group into a cavity within each voltage-sensing domain (VSD), revealing an unobserved binding mode for PIP. Retigabine nestles in each fenestration, inducing local shifts. Instead of staying within the central pore, linopirdine resides in a cytosolic cavity underneath the inner gate. Electrophysiological analyses of various mutants corroborated the structural observations. Our studies reveal the molecular basis for the modulatory mechanism of neuronal KCNQ channels and provide a framework for structure-facilitated drug discovery targeting these important channels.

PubMed: 33238160
DOI: 10.1016/j.molcel.2020.10.037

Experimental method

ELECTRON MICROSCOPY (2.5 Å)