7VNP

Structure of human KCNQ4-ML213 complex with PIP2

Summary for 7VNP

• Entry DOI: 10.2210/pdb7vnp/pdb
• EMDB information: 32044
• Descriptor: Potassium voltage-gated channel subfamily KQT member 4,Maltodextrin-binding protein, 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: kcnq4, ml213, pip2, cryo-em, membrane protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 8
• Total formula weight: 543138.29

Authors

Xu, F.,Zheng, Y. (deposition date: 2021-10-11, release date: 2021-12-01, Last modification date: 2024-06-19)

Primary citation

Zheng, Y.,Liu, H.,Chen, Y.,Dong, S.,Wang, F.,Wang, S.,Li, G.L.,Shu, Y.,Xu, F.
Structural insights into the lipid and ligand regulation of a human neuronal KCNQ channel.
Neuron, 110:237-, 2022

PubMed Abstract: The KCNQ family (KCNQ1-KCNQ5) of voltage-gated potassium channels plays critical roles in many physiological and pathological processes. It is known that the channel opening of all KCNQs relies on the signaling lipid molecule phosphatidylinositol 4,5-bisphosphate (PIP2). However, the molecular mechanism of PIP2 in modulating the opening of the four neuronal KCNQ channels (KCNQ2-KCNQ5), which are essential for regulating neuronal excitability, remains largely elusive. Here, we report the cryoelectron microscopy (cryo-EM) structures of human KCNQ4 determined in complex with the activator ML213 in the absence or presence of PIP2. Two PIP2 molecules are identified in the open-state structure of KCNQ4, which act as a bridge to couple the voltage-sensing domain (VSD) and pore domain (PD) of KCNQ4 leading to the channel opening. Our findings reveal the binding sites and activation mechanisms of ML213 and PIP2 for neuronal KCNQ channels, providing a framework for therapeutic intervention targeting on these important channels.

PubMed: 34767770
DOI: 10.1016/j.neuron.2021.10.029

Experimental method

ELECTRON MICROSCOPY (2.79 Å)