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- EMDB-30244: Cryo-EM structure of human KCNQ4 -

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Basic information

Entry
Database: EMDB / ID: EMD-30244
TitleCryo-EM structure of human KCNQ4
Map data
Sample
  • Complex: Complex of human KCNQ4 and Calmodulin
    • 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 IONPotassium
  • Ligand: water
KeywordsKCNQ / Channel / Calmodulin / PIP2 / MEMBRANE PROTEIN
Function / homology
Function and homology information


Voltage gated Potassium channels / Sensory processing of sound by outer hair cells of the cochlea / Sensory processing of sound by inner hair cells of the cochlea / negative regulation of high voltage-gated calcium channel activity / inner ear morphogenesis / negative regulation of calcium ion export across plasma membrane / regulation of cardiac muscle cell action potential / positive regulation of ryanodine-sensitive calcium-release channel activity / regulation of cell communication by electrical coupling involved in cardiac conduction / negative regulation of peptidyl-threonine phosphorylation ...Voltage gated Potassium channels / Sensory processing of sound by outer hair cells of the cochlea / Sensory processing of sound by inner hair cells of the cochlea / negative regulation of high voltage-gated calcium channel activity / inner ear morphogenesis / negative regulation of calcium ion export across plasma membrane / regulation of cardiac muscle cell action potential / positive regulation of ryanodine-sensitive calcium-release channel activity / regulation of cell communication by electrical coupling involved in cardiac conduction / negative regulation of peptidyl-threonine phosphorylation / protein phosphatase activator activity / voltage-gated potassium channel activity / positive regulation of cyclic-nucleotide phosphodiesterase activity / potassium channel activity / positive regulation of phosphoprotein phosphatase activity / adenylate cyclase binding / catalytic complex / detection of calcium ion / negative regulation of ryanodine-sensitive calcium-release channel activity / regulation of cardiac muscle contraction / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / voltage-gated potassium channel complex / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / regulation of calcium-mediated signaling / positive regulation of protein dephosphorylation / titin binding / positive regulation of protein autophosphorylation / potassium ion transmembrane transport / sperm midpiece / calcium channel complex / substantia nigra development / adenylate cyclase activator activity / regulation of heart rate / protein serine/threonine kinase activator activity / bioluminescence / sarcomere / basal plasma membrane / positive regulation of peptidyl-threonine phosphorylation / regulation of cytokinesis / generation of precursor metabolites and energy / spindle microtubule / sensory perception of sound / positive regulation of protein serine/threonine kinase activity / potassium ion transport / spindle pole / response to calcium ion / calcium-dependent protein binding / G2/M transition of mitotic cell cycle / myelin sheath / vesicle / transmembrane transporter binding / G protein-coupled receptor signaling pathway / centrosome / calcium ion binding / 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 / EF-Hand 1, calcium-binding site ...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. / Ion transport domain / Ion transport protein / EF-hand domain / 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: 2.5 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-
UpdateMar 27, 2024-
Current statusMar 27, 2024Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.0129
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.0129
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7byl
  • Surface level: 0.0129
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_30244.png

Downloads & links

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Map

FileDownload / File: emd_30244.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.087 Å
Density
Contour LevelBy AUTHOR: 0.0129 / Movie #1: 0.0129
Minimum - Maximum-0.025300905 - 0.07295913
Average (Standard dev.)-0.000093964874 (±0.0018198447)
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-0.0250.073-0.000

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Supplemental data

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Additional map: TMD masked

Fileemd_30244_additional_1.map
AnnotationTMD masked
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 Calmodulin

EntireName: Complex of human KCNQ4 and Calmodulin
Components
  • Complex: Complex of human KCNQ4 and Calmodulin
    • 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 IONPotassium
  • Ligand: water

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Supramolecule #1: Complex of human KCNQ4 and Calmodulin

SupramoleculeName: Complex of human KCNQ4 and Calmodulin / 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: 4 / Formula: K
Molecular weightTheoretical: 39.098 Da

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Macromolecule #5: water

MacromoleculeName: water / type: ligand / ID: 5 / Number of copies: 12 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER / Water

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

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Image processing

Startup modelType of model: EMDB MAP
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 192507

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