7CR1

human KCNQ2 in complex with ztz240

Summary for 7CR1

• Entry DOI: 10.2210/pdb7cr1/pdb
• Related: 7CR0
• EMDB information: 30444
• Descriptor: Potassium voltage-gated channel subfamily KQT member 2, N-(6-chloranylpyridin-3-yl)-4-fluoranyl-benzamide (2 entities in total)
• Functional Keywords: ion channel, transport protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 295513.87

Authors

Li, X.,Lv, D.,Wang, J.,Ye, S.,Guo, J. (deposition date: 2020-08-12, release date: 2020-09-16, Last modification date: 2024-03-27)

Primary citation

Li, X.,Zhang, Q.,Guo, P.,Fu, J.,Mei, L.,Lv, D.,Wang, J.,Lai, D.,Ye, S.,Yang, H.,Guo, J.
Molecular basis for ligand activation of the human KCNQ2 channel.
Cell Res., 31:52-61, 2021

PubMed Abstract: The voltage-gated potassium channel KCNQ2 is responsible for M-current in neurons and is an important drug target to treat epilepsy, pain and several other diseases related to neuronal hyper-excitability. A list of synthetic compounds have been developed to directly activate KCNQ2, yet our knowledge of their activation mechanism is limited, due to lack of high-resolution structures. Here, we report cryo-electron microscopy (cryo-EM) structures of the human KCNQ2 determined in apo state and in complex with two activators, ztz240 or retigabine, which activate KCNQ2 through different mechanisms. The activator-bound structures, along with electrophysiology analysis, reveal that ztz240 binds at the voltage-sensing domain and directly stabilizes it at the activated state, whereas retigabine binds at the pore domain and activates the channel by an allosteric modulation. By accurately defining ligand-binding sites, these KCNQ2 structures not only reveal different ligand recognition and activation mechanisms, but also provide a structural basis for drug optimization and design.

PubMed: 32884139
DOI: 10.1038/s41422-020-00410-8

Experimental method

ELECTRON MICROSCOPY (3.4 Å)