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- EMDB-30246: Cryo-EM structure of human KCNQ4 with linopirdine -

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Basic information

Entry
Database: EMDB / ID: EMD-30246
TitleCryo-EM structure of human KCNQ4 with linopirdine
Map data
Sample
  • Complex: Complex of human KCNQ4 and linopirdine
    • Protein or peptide: Green fluorescent protein,Potassium voltage-gated channel subfamily KQT member 4
    • Protein or peptide: Calmodulin-3
  • Ligand: [(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
  • Ligand: POTASSIUM ION
  • Ligand: 1-phenyl-3,3-bis(pyridin-4-ylmethyl)indol-2-one
KeywordsKCNQ / Channel / Calmodulin / PIP2 / linopirdine / MEMBRANE PROTEIN
Function / homology
Function and homology information


transporter inhibitor activity / Voltage gated Potassium channels / establishment of protein localization to mitochondrial membrane / type 3 metabotropic glutamate receptor binding / Sensory processing of sound by outer hair cells of the cochlea / Sensory processing of sound by inner hair cells of the cochlea / inner ear morphogenesis / response to corticosterone / negative regulation of high voltage-gated calcium channel activity / negative regulation of calcium ion export across plasma membrane ...transporter inhibitor activity / Voltage gated Potassium channels / establishment of protein localization to mitochondrial membrane / type 3 metabotropic glutamate receptor binding / Sensory processing of sound by outer hair cells of the cochlea / Sensory processing of sound by inner hair cells of the cochlea / inner ear morphogenesis / response to corticosterone / negative regulation of high voltage-gated calcium channel activity / negative regulation of calcium ion export across plasma membrane / regulation of cardiac muscle cell action potential / presynaptic endocytosis / nitric-oxide synthase binding / regulation of cell communication by electrical coupling involved in cardiac conduction / regulation of synaptic vesicle exocytosis / calcineurin-mediated signaling / adenylate cyclase binding / protein phosphatase activator activity / voltage-gated potassium channel activity / catalytic complex / detection of calcium ion / regulation of synaptic vesicle endocytosis / regulation of cardiac muscle contraction / potassium channel activity / postsynaptic cytosol / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / phosphatidylinositol 3-kinase binding / presynaptic cytosol / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / titin binding / sperm midpiece / regulation of calcium-mediated signaling / voltage-gated potassium channel complex / potassium ion transmembrane transport / calcium channel complex / substantia nigra development / regulation of heart rate / basal plasma membrane / calyx of Held / bioluminescence / response to amphetamine / adenylate cyclase activator activity / sarcomere / protein serine/threonine kinase activator activity / nitric-oxide synthase regulator activity / regulation of cytokinesis / generation of precursor metabolites and energy / spindle microtubule / calcium channel regulator activity / sensory perception of sound / response to calcium ion / mitochondrial membrane / potassium ion transport / G2/M transition of mitotic cell cycle / Schaffer collateral - CA1 synapse / long-term synaptic potentiation / spindle pole / calcium-dependent protein binding / synaptic vesicle membrane / myelin sheath / growth cone / vesicle / transmembrane transporter binding / G protein-coupled receptor signaling pathway / protein domain specific binding / calcium ion binding / centrosome / protein kinase binding / protein-containing complex / nucleus / plasma membrane / cytoplasm
Similarity search - Function
Potassium channel, voltage dependent, KCNQ / Potassium channel, voltage dependent, KCNQ, C-terminal / KCNQ voltage-gated potassium channel / : / Green fluorescent protein, GFP / Green fluorescent protein-related / Green fluorescent protein / Green fluorescent protein / EF-hand domain pair / EF-hand, calcium binding motif ...Potassium channel, voltage dependent, KCNQ / Potassium channel, voltage dependent, KCNQ, C-terminal / KCNQ voltage-gated potassium channel / : / Green fluorescent protein, GFP / Green fluorescent protein-related / Green fluorescent protein / Green fluorescent protein / EF-hand domain pair / EF-hand, calcium binding motif / EF-Hand 1, calcium-binding site / EF-hand calcium-binding domain. / EF-hand calcium-binding domain profile. / EF-hand domain / Ion transport domain / Ion transport protein / EF-hand domain pair
Similarity search - Domain/homology
Calmodulin-3 / Green fluorescent protein / Potassium voltage-gated channel subfamily KQT member 4
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsShen H / Li T
CitationJournal: Mol Cell / Year: 2021
Title: Structural Basis for the Modulation of Human KCNQ4 by Small-Molecule Drugs.
Authors: Tian Li / Kun Wu / Zhenlei Yue / Yifei Wang / Fan Zhang / Huaizong Shen /
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 ...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.
History
DepositionApr 23, 2020-
Header (metadata) releaseDec 2, 2020-
Map releaseDec 2, 2020-
UpdateJun 18, 2025-
Current statusJun 18, 2025Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.0185
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.0185
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7byn
  • Surface level: 0.0185
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_30246.png

Downloads & links

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Map

FileDownload / File: emd_30246.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.09 Å/pix.
x 320 pix.
= 347.84 Å		1.09 Å/pix.
x 320 pix.
= 347.84 Å		1.09 Å/pix.
x 320 pix.
= 347.84 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.087 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0185 / Movie #1: 0.0185
Minimum - Maximum-0.07460385 - 0.14175409
Average (Standard dev.)-0.000033173896 (±0.0025447437)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 347.84 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0871.0871.087
M x/y/z320320320
origin x/y/z0.0000.0000.000
length x/y/z347.840347.840347.840
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ360360360
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS320320320
D min/max/mean-0.0750.142-0.000

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Supplemental data

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Additional map: #1

Fileemd_30246_additional_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Complex of human KCNQ4 and linopirdine

EntireName: Complex of human KCNQ4 and linopirdine
Components
  • Complex: Complex of human KCNQ4 and linopirdine
    • Protein or peptide: Green fluorescent protein,Potassium voltage-gated channel subfamily KQT member 4
    • Protein or peptide: Calmodulin-3
  • Ligand: [(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
  • Ligand: POTASSIUM ION
  • Ligand: 1-phenyl-3,3-bis(pyridin-4-ylmethyl)indol-2-one

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Supramolecule #1: Complex of human KCNQ4 and linopirdine

SupramoleculeName: Complex of human KCNQ4 and linopirdine / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Green fluorescent protein,Potassium voltage-gated channel subfami...

MacromoleculeName: Green fluorescent protein,Potassium voltage-gated channel subfamily KQT member 4
type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 109.327836 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MHHHHHHHHA ADYKDHDIDY KDDDDKSAMV SKGEELFTGV VPILVELDGD VNGHKFSVSG EGEGDATYGK LTLKFICTTG KLPVPWPTL VTTLTYGVQC FSRYPDHMKQ HDFFKSAMPE GYVQERTIFF KDDGNYTTRA EVKFEGDTLV NRIELKGIDF K EDGNILGH ...String:
MHHHHHHHHA ADYKDHDIDY KDDDDKSAMV SKGEELFTGV VPILVELDGD VNGHKFSVSG EGEGDATYGK LTLKFICTTG KLPVPWPTL VTTLTYGVQC FSRYPDHMKQ HDFFKSAMPE GYVQERTIFF KDDGNYTTRA EVKFEGDTLV NRIELKGIDF K EDGNILGH KLEYNYNSHN VYIMADKQKN GIKVNFKIRH NIEDGSVQLA DHYQQNTPIG DGPVLLPDNH YLSTQSKLSK DP NEKRDHM VLLEFVTAAG ITLGMDELYK SGLRSGLEVL FQGPGGRMAE APPRRLGLGP PPGDAPRAEL VALTAVQSEQ GEA GGGGSP RRLGLLGSPL PPGAPLPGPG SGSGSACGQR SSAAHKRYRR LQNWVYNVLE RPRGWAFVYH VFIFLLVFSC LVLS VLSTI QEHQELANEC LLILEFVMIV VFGLEYIVRV WSAGCCCRYR GWQGRFRFAR KPFCVIDFIV FVASVAVIAA GTQGN IFAT SALRSMRFLQ ILRMVRMDRR GGTWKLLGSV VYAHSKELIT AWYIGFLVLI FASFLVYLAE KDANSDFSSY ADSLWW GTI TLTTIGYGDK TPHTWLGRVL AAGFALLGIS FFALPAGILG SGFALKVQEQ HRQKHFEKRR MPAANLIQAA WRLYSTD MS RAYLTATWYY YDSILPSFRE LALLFEHVQR ARNGGLRPLE VRRAPVPDGA PSRYPPVATC HRPGSTSFCP GESSRMGI K DRIRMGSSQR RTGPSKQHLA PPTMPTSPSS EQVGEATSPT KVQKSWSFND RTRFRASLRL KPRTSAEDAP SEEVAEEKS YQCELTVDDI MPAVKTVIRS IRILKFLVAK RKFKETLRPY DVKDVIEQYS AGHLDMLGRI KSLQTRVDQI VGRGPGDRKA REKGDKGPS DAEVVDEISM MGRVVKVEKQ VQSIEHKLDL LLGFYSRCLR SGTSASLGAV QVPLFDPDIT SDYHSPVDHE D ISVSAQTL SISRSVSTNM D

UniProtKB: Green fluorescent protein, Potassium voltage-gated channel subfamily KQT member 4

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Macromolecule #2: Calmodulin-3

MacromoleculeName: Calmodulin-3 / type: protein_or_peptide / ID: 2 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 16.852545 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
MADQLTEEQI AEFKEAFSLF DKDGDGTITT KELGTVMRSL GQNPTEAELQ DMINEVDADG NGTIDFPEFL TMMARKMKDT DSEEEIREA FRVFDKDGNG YISAAELRHV MTNLGEKLTD EEVDEMIREA DIDGDGQVNY EEFVQMMTAK

UniProtKB: Calmodulin-3

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Macromolecule #3: [(2R)-1-octadecanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tr...

MacromoleculeName: [(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
type: ligand / ID: 3 / Number of copies: 4 / Formula: PT5
Molecular weightTheoretical: 1.047088 KDa

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Macromolecule #4: POTASSIUM ION

MacromoleculeName: POTASSIUM ION / type: ligand / ID: 4 / Number of copies: 3 / Formula: K
Molecular weightTheoretical: 39.098 Da

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Macromolecule #5: 1-phenyl-3,3-bis(pyridin-4-ylmethyl)indol-2-one

MacromoleculeName: 1-phenyl-3,3-bis(pyridin-4-ylmethyl)indol-2-one / type: ligand / ID: 5 / Number of copies: 1 / Formula: FCC
Molecular weightTheoretical: 391.464 Da
Chemical component information

ChemComp-FCC:
1-phenyl-3,3-bis(pyridin-4-ylmethyl)indol-2-one

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: NONE
Startup modelType of model: EMDB MAP
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 229040
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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