|Entry||Database: PDB / ID: 7cr0|
|Title||human KCNQ2 in apo state|
|Components||Potassium voltage-gated channel subfamily KQT member 2|
|Keywords||TRANSPORT PROTEIN / ion channel|
|Function / homology|
Function and homology information
axon initial segment / delayed rectifier potassium channel activity / node of Ranvier / ankyrin binding / potassium ion transmembrane transport / voltage-gated potassium channel complex / voltage-gated potassium channel activity / regulation of ion transmembrane transport / nervous system development / chemical synaptic transmission ...axon initial segment / delayed rectifier potassium channel activity / node of Ranvier / ankyrin binding / potassium ion transmembrane transport / voltage-gated potassium channel complex / voltage-gated potassium channel activity / regulation of ion transmembrane transport / nervous system development / chemical synaptic transmission / calmodulin binding / synapse / integral component of plasma membrane / integral component of membrane / plasma membrane
Voltage-gated potassium channel / Ankyrin-G binding site / Potassium channel, voltage dependent, KCNQ, C-terminal / Ion transport domain / Potassium channel, voltage dependent, KCNQ2 / Potassium channel, voltage dependent, KCNQ
Potassium voltage-gated channel subfamily KQT member 2
|Biological species||Homo sapiens (human)|
|Method||ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å|
|Authors||Li, X. / Lv, D. / Wang, J. / Ye, S. / Guo, J.|
|Funding support|| China, 2items |
|Citation||Journal: Cell Res. / Year: 2020|
Title: Molecular basis for ligand activation of the human KCNQ2 channel.
Authors: Xiaoxiao Li / Qiansen Zhang / Peipei Guo / Jie Fu / Lianghe Mei / Dashuai Lv / Jiangqin Wang / Dongwu Lai / Sheng Ye / Huaiyu Yang / Jiangtao Guo /
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- ...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.
SummaryFull reportAbout validation report
|Structure viewer||Molecule: |
Downloads & links
A: Potassium voltage-gated channel subfamily KQT member 2
B: Potassium voltage-gated channel subfamily KQT member 2
C: Potassium voltage-gated channel subfamily KQT member 2
D: Potassium voltage-gated channel subfamily KQT member 2
Mass: 73627.812 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KCNQ2 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: O43526
|Experiment||Method: ELECTRON MICROSCOPY|
|EM experiment||Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction|
|Component||Name: voltage-gated potassium channel KCNQ2 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT|
|Source (natural)||Organism: Homo sapiens (human)|
|Source (recombinant)||Organism: Homo sapiens (human)|
|Buffer solution||pH: 8|
|Specimen||Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES|
|Vitrification||Cryogen name: ETHANE|
-Electron microscopy imaging
Model: Titan Krios / Image courtesy: FEI Company
|Microscopy||Model: FEI TITAN KRIOS|
|Electron gun||Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM|
|Electron lens||Mode: BRIGHT FIELDBright-field microscopy|
|Image recording||Electron dose: 1.556 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)|
|Software||Name: PHENIX / Version: 1.15.2_3472: / Classification: refinement|
|CTF correction||Type: PHASE FLIPPING AND AMPLITUDE CORRECTION|
|3D reconstruction||Resolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 145412 / Symmetry type: POINT|
|Refine LS restraints|
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