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- EMDB-30447: human KCNQ2-CaM in complex with ztz240 -

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Basic information

Entry
Database: EMDB / ID: EMD-30447
Titlehuman KCNQ2-CaM in complex with ztz240
Map data
Samplevoltage-gated potassium channel KCNQ2
  • Potassium voltage-gated channel subfamily KQT member 2
  • Calmodulin-3
  • ligand
Function / homology
Function and homology information


axon initial segment / establishment of protein localization to mitochondrial membrane / type 3 metabotropic glutamate receptor binding / delayed rectifier potassium channel activity / regulation of high voltage-gated calcium channel activity / node of Ranvier / regulation of synaptic vesicle endocytosis / response to corticosterone / ankyrin binding / activation of adenylate cyclase activity ...axon initial segment / establishment of protein localization to mitochondrial membrane / type 3 metabotropic glutamate receptor binding / delayed rectifier potassium channel activity / regulation of high voltage-gated calcium channel activity / node of Ranvier / regulation of synaptic vesicle endocytosis / response to corticosterone / ankyrin binding / activation of adenylate cyclase activity / N-terminal myristoylation domain binding / nitric-oxide synthase binding / regulation of cell communication by electrical coupling involved in cardiac conduction / protein phosphatase activator activity / negative regulation of peptidyl-threonine phosphorylation / positive regulation of ryanodine-sensitive calcium-release channel activity / potassium ion transmembrane transport / positive regulation of cyclic-nucleotide phosphodiesterase activity / adenylate cyclase binding / detection of calcium ion / catalytic complex / voltage-gated potassium channel complex / adenylate cyclase activator activity / voltage-gated potassium channel activity / negative regulation of ryanodine-sensitive calcium-release channel activity / regulation of cardiac muscle contraction / regulation of ion transmembrane transport / positive regulation of protein dephosphorylation / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / phosphatidylinositol 3-kinase binding / positive regulation of phosphoprotein phosphatase activity / mitochondrial membrane / response to amphetamine / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / titin binding / substantia nigra development / calcium channel complex / synaptic vesicle membrane / sarcomere / regulation of heart rate / protein serine/threonine kinase activator activity / nitric-oxide synthase regulator activity / positive regulation of protein autophosphorylation / enzyme regulator activity / positive regulation of DNA binding / spindle microtubule / positive regulation of peptidyl-threonine phosphorylation / positive regulation of protein serine/threonine kinase activity / regulation of cytokinesis / regulation of synaptic vesicle exocytosis / calcium-mediated signaling / positive regulation of nitric-oxide synthase activity / calcium-dependent protein binding / nervous system development / response to calcium ion / microtubule cytoskeleton organization / spindle pole / growth cone / G2/M transition of mitotic cell cycle / myelin sheath / chemical synaptic transmission / disordered domain specific binding / ion channel binding / vesicle / calmodulin binding / centrosome / G protein-coupled receptor signaling pathway / synapse / protein domain specific binding / calcium ion binding / protein kinase binding / integral component of plasma membrane / protein-containing complex / integral component of membrane / plasma membrane / nucleus / cytoplasm
Potassium channel, voltage dependent, KCNQ / Ankyrin-G binding site / Potassium channel, voltage dependent, KCNQ2 / Ion transport domain / EF-hand domain pair / Potassium channel, voltage dependent, KCNQ, C-terminal / EF-Hand 1, calcium-binding site / Voltage-gated potassium channel / Calmodulin / EF-hand domain
Potassium voltage-gated channel subfamily KQT member 2 / Calmodulin-3
Biological speciesHomo sapiens (human) / Human (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.9 Å
AuthorsLi X / Lv D / Wang J / Ye S / Guo J
Funding support China, 2 items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China)2018YFA0508100 China
National Natural Science Foundation of China (NSFC)31870724 China
CitationJournal: 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.
Validation ReportPDB-ID: 7cr4

SummaryFull reportAbout validation report
History
DepositionAug 12, 2020-
Header (metadata) releaseSep 16, 2020-
Map releaseSep 16, 2020-
UpdateSep 16, 2020-
Current statusSep 16, 2020Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.01
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.01
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7cr4
  • Surface level: 0.01
  • Imaged by UCSF Chimera
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Structure viewerEM map:
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Supplemental images

Downloads & links

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Map

FileDownload / File: emd_30447.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.01 Å/pix.
x 240 pix.
= 243.36 Å
1.01 Å/pix.
x 240 pix.
= 243.36 Å
1.01 Å/pix.
x 240 pix.
= 243.36 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.014 Å
Density
Contour LevelBy AUTHOR: 0.01 / Movie #1: 0.01
Minimum - Maximum-0.024261808 - 0.039428234
Average (Standard dev.)-0.0000146376 (±0.0021366016)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions240240240
Spacing240240240
CellA=B=C: 243.36002 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0141.0141.014
M x/y/z240240240
origin x/y/z0.0000.0000.000
length x/y/z243.360243.360243.360
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS240240240
D min/max/mean-0.0240.039-0.000

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Supplemental data

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Sample components

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Entire voltage-gated potassium channel KCNQ2

EntireName: voltage-gated potassium channel KCNQ2 / Number of components: 4

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Component #1: protein, voltage-gated potassium channel KCNQ2

ProteinName: voltage-gated potassium channel KCNQ2 / Recombinant expression: No
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Homo sapiens (human)

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Component #2: protein, Potassium voltage-gated channel subfamily KQT member 2

ProteinName: Potassium voltage-gated channel subfamily KQT member 2
Number of Copies: 4 / Recombinant expression: No
MassTheoretical: 73.627812 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Homo sapiens (human)

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Component #3: protein, Calmodulin-3

ProteinName: Calmodulin-3 / Number of Copies: 4 / Recombinant expression: No
MassTheoretical: 16.852545 kDa
SourceSpecies: Human (human)

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Component #4: ligand, N-(6-chloranylpyridin-3-yl)-4-fluoranyl-benzamide

LigandName: N-(6-chloranylpyridin-3-yl)-4-fluoranyl-benzamide / Number of Copies: 4 / Recombinant expression: No
MassTheoretical: 0.250656 kDa

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Experimental details

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Sample preparation

SpecimenSpecimen state: Particle / Method: cryo EM
Sample solutionpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
ImagingMicroscope: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Electron dose: 1.556 e/Å2 / Illumination mode: FLOOD BEAM
LensImaging mode: BRIGHT FIELD
Specimen HolderModel: OTHER
CameraDetector: GATAN K2 SUMMIT (4k x 4k)

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Image processing

ProcessingMethod: single particle reconstruction / Number of projections: 86371
3D reconstructionResolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF

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Atomic model buiding

Output model

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