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- EMDB-32046: Structure of human KCNQ4-ML213 complex in digitonin -

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Basic information

Entry
Database: EMDB / ID: EMD-32046
TitleStructure of human KCNQ4-ML213 complex in digitonin
Map data
Sample
  • Complex: KCNQ4-ML213 complex in digitonin
    • Protein or peptide: Potassium voltage-gated channel subfamily KQT member 4,Maltodextrin-binding protein
    • Protein or peptide: Calmodulin-3
  • Ligand: (1S,2S,4R)-N-(2,4,6-trimethylphenyl)bicyclo[2.2.1]heptane-2-carboxamid
  • Ligand: POTASSIUM ION
KeywordsKCNQ4 / ML213 / cryo-EM / digitonin / 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 / inner ear morphogenesis / negative regulation of high voltage-gated calcium channel activity / positive regulation of cyclic-nucleotide phosphodiesterase activity / 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 ...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 / inner ear morphogenesis / negative regulation of high voltage-gated calcium channel activity / positive regulation of cyclic-nucleotide phosphodiesterase activity / 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 / negative regulation of ryanodine-sensitive calcium-release channel activity / protein phosphatase activator activity / : / adenylate cyclase binding / voltage-gated potassium channel activity / catalytic complex / carbohydrate transmembrane transporter activity / potassium channel activity / detection of calcium ion / 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 / : / titin binding / positive regulation of protein autophosphorylation / regulation of calcium-mediated signaling / sperm midpiece / calcium channel complex / potassium ion transmembrane transport / substantia nigra development / adenylate cyclase activator activity / regulation of heart rate / sarcomere / protein serine/threonine kinase activator activity / basal plasma membrane / regulation of cytokinesis / positive regulation of peptidyl-threonine phosphorylation / 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 / outer membrane-bounded periplasmic space / 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 / : / Maltose/Cyclodextrin ABC transporter, substrate-binding protein / Solute-binding family 1, conserved site / Bacterial extracellular solute-binding proteins, family 1 signature. / Bacterial extracellular solute-binding protein / Bacterial extracellular solute-binding protein / EF-hand domain pair ...Potassium channel, voltage dependent, KCNQ / Potassium channel, voltage dependent, KCNQ, C-terminal / KCNQ voltage-gated potassium channel / : / Maltose/Cyclodextrin ABC transporter, substrate-binding protein / Solute-binding family 1, conserved site / Bacterial extracellular solute-binding proteins, family 1 signature. / Bacterial extracellular solute-binding protein / Bacterial extracellular solute-binding 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
Maltodextrin-binding protein / Calmodulin-3 / Potassium voltage-gated channel subfamily KQT member 4
Similarity search - Component
Biological speciesHomo sapiens (human) / Escherichia coli (strain B / BL21-DE3) (bacteria)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsXu F / Zheng Y
Funding support China, 1 items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China)2018YFA0507000 China
CitationJournal: Neuron / Year: 2022
Title: Structural insights into the lipid and ligand regulation of a human neuronal KCNQ channel.
Authors: You Zheng / Heng Liu / Yuxin Chen / Shaowei Dong / Fang Wang / Shengyi Wang / Geng-Lin Li / Yilai Shu / Fei Xu /
Abstract: The KCNQ family (KCNQ1-KCNQ5) of voltage-gated potassium channels plays critical roles in many physiological and pathological processes. It is known that the channel opening of all KCNQs relies on ...The KCNQ family (KCNQ1-KCNQ5) of voltage-gated potassium channels plays critical roles in many physiological and pathological processes. It is known that the channel opening of all KCNQs relies on the signaling lipid molecule phosphatidylinositol 4,5-bisphosphate (PIP2). However, the molecular mechanism of PIP2 in modulating the opening of the four neuronal KCNQ channels (KCNQ2-KCNQ5), which are essential for regulating neuronal excitability, remains largely elusive. Here, we report the cryoelectron microscopy (cryo-EM) structures of human KCNQ4 determined in complex with the activator ML213 in the absence or presence of PIP2. Two PIP2 molecules are identified in the open-state structure of KCNQ4, which act as a bridge to couple the voltage-sensing domain (VSD) and pore domain (PD) of KCNQ4 leading to the channel opening. Our findings reveal the binding sites and activation mechanisms of ML213 and PIP2 for neuronal KCNQ channels, providing a framework for therapeutic intervention targeting on these important channels.
History
DepositionOct 11, 2021-
Header (metadata) releaseDec 1, 2021-
Map releaseDec 1, 2021-
UpdateJun 19, 2024-
Current statusJun 19, 2024Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.06
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.06
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7vnr
  • Surface level: 0.06
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-7vnr
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_32046.png

Downloads & links

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Map

FileDownload / File: emd_32046.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.)
0.82 Å/pix.
x 320 pix.
= 262.4 Å		0.82 Å/pix.
x 320 pix.
= 262.4 Å		0.82 Å/pix.
x 320 pix.
= 262.4 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.82 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.052 / Movie #1: 0.06
Minimum - Maximum-0.25183332 - 0.50700927
Average (Standard dev.)0.00030571726 (±0.012754416)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 262.4 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.820.820.82
M x/y/z320320320
origin x/y/z0.0000.0000.000
length x/y/z262.400262.400262.400
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ400400400
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS320320320
D min/max/mean-0.2520.5070.000

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Supplemental data

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Sample components

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Entire : KCNQ4-ML213 complex in digitonin

EntireName: KCNQ4-ML213 complex in digitonin
Components
  • Complex: KCNQ4-ML213 complex in digitonin
    • Protein or peptide: Potassium voltage-gated channel subfamily KQT member 4,Maltodextrin-binding protein
    • Protein or peptide: Calmodulin-3
  • Ligand: (1S,2S,4R)-N-(2,4,6-trimethylphenyl)bicyclo[2.2.1]heptane-2-carboxamid
  • Ligand: POTASSIUM ION

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Supramolecule #1: KCNQ4-ML213 complex in digitonin

SupramoleculeName: KCNQ4-ML213 complex in digitonin / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Potassium voltage-gated channel subfamily KQT member 4,Maltodextr...

MacromoleculeName: Potassium voltage-gated channel subfamily KQT member 4,Maltodextrin-binding protein
type: protein_or_peptide / ID: 1
Details: The fusion protein of Potassium voltage-gated channel subfamily KQT member 4, linker, and Maltodextrin-binding protein
Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Escherichia coli (strain B / BL21-DE3) (bacteria) / Strain: B / BL21-DE3
Molecular weightTheoretical: 116.541383 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MDYKDDDDKA EAPPRRLGLG PPPGDAPRAE LVALTAVQSE QGEAGGGGSP RRLGLLGSPL PPGAPLPGPG SGSGSACGQR SSAAHKRYR RLQNWVYNVL ERPRGWAFVY HVFIFLLVFS CLVLSVLSTI QEHQELANEC LLILEFVMIV VFGLEYIVRV W SAGCCCRY ...String:
MDYKDDDDKA EAPPRRLGLG PPPGDAPRAE LVALTAVQSE QGEAGGGGSP RRLGLLGSPL PPGAPLPGPG SGSGSACGQR SSAAHKRYR RLQNWVYNVL ERPRGWAFVY HVFIFLLVFS CLVLSVLSTI QEHQELANEC LLILEFVMIV VFGLEYIVRV W SAGCCCRY RGWQGRFRFA RKPFCVIDFI VFVASVAVIA AGTQGNIFAT SALRSMRFLQ ILRMVRMDRR GGTWKLLGSV VY AHSKELI TAWYIGFLVL IFASFLVYLA EKDANSDFSS YADSLWWGTI TLTTIGYGDK TPHTWLGRVL AAGFALLGIS FFA LPAGIL GSGFALKVQE QHRQKHFEKR RMPAANLIQA AWRLYSTDMS RAYLTATWYY YDSILPSFRE LALLFEHVQR ARNG GLRPL EVRRAPVPDG APSRYPPVAT CHRPGSTSFC PGESSRMGIK DRIRMGSSQR RTGPSKQHLA PPTMPTSPSS EQVGE ATSP TKVQKSWSFN DRTRFRASLR LKPRTSAEDA PSEEVAEEKS YQCELTVDDI MPAVKTVIRS IRILKFLVAK RKFKET LRP YDVKDVIEQY SAGHLDMLGR IKSLQTRVDQ IVGRGPGDRK AREKGDKGPS DAEVVDEISM MGRVVKVEKQ VQSIEHK LD LLLGFYSRCL RSGTSALEVL FQGPMAKIEE GKLVIWINGD KGYNGLAEVG KKFEKDTGIK VTVEHPDKLE EKFPQVAA T GDGPDIIFWA HDRFGGYAQS GLLAEITPDK AFQDKLYPFT WDAVRYNGKL IAYPIAVEAL SLIYNKDLLP NPPKTWEEI PALDKELKAK GKSALMFNLQ EPYFTWPLIA ADGGYAFKYE NGKYDIKDVG VDNAGAKAGL TFLVDLIKNK HMNADTDYSI AEAAFNKGE TAMTINGPWA WSNIDTSKVN YGVTVLPTFK GQPSKPFVGV LSAGINAASP NKELAKEFLE NYLLTDEGLE A VNKDKPLG AVALKSYEEE LAKDPRIAAT MENAQKGEIM PNIPQMSAFW YAVRTAVINA ASGRQTVDEA LKDAQTNAAA EH HHHHHHH HH

UniProtKB: Potassium voltage-gated channel subfamily KQT member 4, Maltodextrin-binding protein

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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: (1S,2S,4R)-N-(2,4,6-trimethylphenyl)bicyclo[2.2.1]heptane-2-carboxamid

MacromoleculeName: (1S,2S,4R)-N-(2,4,6-trimethylphenyl)bicyclo[2.2.1]heptane-2-carboxamid
type: ligand / ID: 3 / Number of copies: 4 / Formula: 7YV
Molecular weightTheoretical: 257.371 Da
Chemical component information

ChemComp-7YV:
(1S,2S,4R)-N-(2,4,6-trimethylphenyl)bicyclo[2.2.1]heptane-2-carboxamid

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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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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration4.8 mg/mL
BufferpH: 7.4
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 45 sec.
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: 16.8 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: DARK FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 126225
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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