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- EMDB-48726: Structure of Xenopus KCNQ1(E150R/R221E)-CaM with the VSD in the i... -

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Basic information

Entry
Database: EMDB / ID: EMD-48726
TitleStructure of Xenopus KCNQ1(E150R/R221E)-CaM with the VSD in the intermediate state
Map data
Sample
  • Complex: Potassium voltage-gated channel subfamily KQT member 1 (E150R/R221E) in complex with calmodulin
    • Protein or peptide: Potassium voltage-gated channel subfamily KQT member 1
    • Protein or peptide: Calmodulin-1
KeywordsPotassium Ion Channel Protein / TRANSPORT PROTEIN
Function / homology
Function and homology information


regulation of gastric acid secretion / membrane repolarization / delayed rectifier potassium channel activity / outward rectifier potassium channel activity / CaM pathway / Cam-PDE 1 activation / intestinal absorption / Sodium/Calcium exchangers / Calmodulin induced events / Reduction of cytosolic Ca++ levels ...regulation of gastric acid secretion / membrane repolarization / delayed rectifier potassium channel activity / outward rectifier potassium channel activity / CaM pathway / Cam-PDE 1 activation / intestinal absorption / Sodium/Calcium exchangers / Calmodulin induced events / Reduction of cytosolic Ca++ levels / Activation of Ca-permeable Kainate Receptor / CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde / Loss of phosphorylation of MECP2 at T308 / CREB1 phosphorylation through the activation of Adenylate Cyclase / CaMK IV-mediated phosphorylation of CREB / PKA activation / negative regulation of high voltage-gated calcium channel activity / Glycogen breakdown (glycogenolysis) / CLEC7A (Dectin-1) induces NFAT activation / Activation of RAC1 downstream of NMDARs / negative regulation of ryanodine-sensitive calcium-release channel activity / organelle localization by membrane tethering / mitochondrion-endoplasmic reticulum membrane tethering / autophagosome membrane docking / negative regulation of calcium ion export across plasma membrane / regulation of cardiac muscle cell action potential / presynaptic endocytosis / renal absorption / Synthesis of IP3 and IP4 in the cytosol / regulation of cell communication by electrical coupling involved in cardiac conduction / Phase 0 - rapid depolarisation / calcineurin-mediated signaling / Negative regulation of NMDA receptor-mediated neuronal transmission / Unblocking of NMDA receptors, glutamate binding and activation / inner ear development / RHO GTPases activate PAKs / Uptake and function of anthrax toxins / Ion transport by P-type ATPases / regulation of ryanodine-sensitive calcium-release channel activity / Long-term potentiation / protein phosphatase activator activity / Calcineurin activates NFAT / Regulation of MECP2 expression and activity / DARPP-32 events / monoatomic ion channel complex / Smooth Muscle Contraction / voltage-gated potassium channel activity / detection of calcium ion / regulation of cardiac muscle contraction / catalytic complex / RHO GTPases activate IQGAPs / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / cellular response to interferon-beta / calcium channel inhibitor activity / Protein methylation / Activation of AMPK downstream of NMDARs / presynaptic cytosol / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / Ion homeostasis / eNOS activation / titin binding / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / sperm midpiece / regulation of calcium-mediated signaling / phosphatidylinositol-4,5-bisphosphate binding / voltage-gated potassium channel complex / potassium ion transmembrane transport / calcium channel complex / FCERI mediated Ca+2 mobilization / substantia nigra development / regulation of heart rate / Ras activation upon Ca2+ influx through NMDA receptor / FCGR3A-mediated IL10 synthesis / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / cytoplasmic vesicle membrane / calyx of Held / adenylate cyclase activator activity / sarcomere / VEGFR2 mediated cell proliferation / protein serine/threonine kinase activator activity / VEGFR2 mediated vascular permeability / regulation of cytokinesis / spindle microtubule / Translocation of SLC2A4 (GLUT4) to the plasma membrane / positive regulation of receptor signaling pathway via JAK-STAT / calcium channel regulator activity / RAF activation / Transcriptional activation of mitochondrial biogenesis / response to calcium ion / cellular response to type II interferon / Stimuli-sensing channels / G2/M transition of mitotic cell cycle / long-term synaptic potentiation / spindle pole / RAS processing / Signaling by RAF1 mutants / calcium-dependent protein binding / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants
Similarity search - Function
Potassium channel, voltage dependent, KCNQ1 / Potassium channel, voltage dependent, KCNQ / Potassium channel, voltage dependent, KCNQ, C-terminal / KCNQ voltage-gated potassium channel / Voltage-dependent channel domain superfamily / : / EF-hand domain pair / EF-hand, calcium binding motif / EF-Hand 1, calcium-binding site / EF-hand calcium-binding domain. ...Potassium channel, voltage dependent, KCNQ1 / Potassium channel, voltage dependent, KCNQ / Potassium channel, voltage dependent, KCNQ, C-terminal / KCNQ voltage-gated potassium channel / Voltage-dependent channel domain superfamily / : / 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-1 / Potassium voltage-gated channel subfamily KQT member 1
Similarity search - Component
Biological speciesXenopus laevis (African clawed frog) / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.53 Å
AuthorsKyriakis E / Russo S / Molinarolo S / Eldstrom J / Van Petegem F / Fedida D
Funding support Canada, 6 items
OrganizationGrant numberCountry
Canadian Institutes of Health Research (CIHR)PJT-156181 Canada
Canadian Institutes of Health Research (CIHR)PJT-518041 Canada
Other governmentG-21-0031566
Other governmentG-24-0036478
Canadian Institutes of Health Research (CIHR)PJT-153305 Canada
Other governmentRT-2022-2735
CitationJournal: Nat Commun / Year: 2025
Title: A physiologically-relevant intermediate state structure of a voltage-gated potassium channel.
Authors: Efthimios Kyriakis / Daniel Sastre / Jodene Eldstrom / Agnese Roscioni / Sophia Russo / Fariba Ataei / Ying Dou / Magnus Chan / Steven Molinarolo / Luca Maragliano / Filip Van Petegem / David Fedida /
Abstract: Voltage-gated potassium ion (K) channels perform critical roles in many physiological processes, while gain- or loss-of-function mutations lead to life-threatening pathologies. Here, we establish the ...Voltage-gated potassium ion (K) channels perform critical roles in many physiological processes, while gain- or loss-of-function mutations lead to life-threatening pathologies. Here, we establish the high-resolution structure of a pivotal intermediate state of the Kv7.1 (KCNQ1) channel using cryogenic electron microscopy. The 3.53 Å resolution structure reveals straightened upper S1 and S2 voltage sensor helices, distancing them from the pore filter helix compared to fully activated channels. The outward translation of the S4 voltage sensor is essentially complete in this intermediate state, and the S4-S6 helices and the S4-S5 linker do not change position significantly between intermediate and activated states. The PIP2 ligand can bind in both states. Movement of S1 and S2 helices towards the filter helix from intermediate to activated states may explain smaller components of KCNQ1 voltage sensor fluorescence, differential Rb/K selectivity, and pharmacological responses to activators and inhibitors. Single channel recordings and the location of long QT mutations suggest the potential physiological and disease importance of the intermediate state.
History
DepositionJan 21, 2025-
Header (metadata) releaseOct 15, 2025-
Map releaseOct 15, 2025-
UpdateOct 15, 2025-
Current statusOct 15, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_48726.png

Downloads & links

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Map

FileDownload / File: emd_48726.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
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AxesZ (Sec.)Y (Row.)X (Col.)
0.96 Å/pix.
x 360 pix.
= 345.6 Å		0.96 Å/pix.
x 360 pix.
= 345.6 Å		0.96 Å/pix.
x 360 pix.
= 345.6 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.96 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.113
Minimum - Maximum-0.3528447 - 0.78215104
Average (Standard dev.)0.001148117 (±0.016980803)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 345.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half map B

Fileemd_48726_half_map_1.map
AnnotationHalf map B
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Half map: Half map A

Fileemd_48726_half_map_2.map
AnnotationHalf map A
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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Entire : Potassium voltage-gated channel subfamily KQT member 1 (E150R/R22...

EntireName: Potassium voltage-gated channel subfamily KQT member 1 (E150R/R221E) in complex with calmodulin
Components
  • Complex: Potassium voltage-gated channel subfamily KQT member 1 (E150R/R221E) in complex with calmodulin
    • Protein or peptide: Potassium voltage-gated channel subfamily KQT member 1
    • Protein or peptide: Calmodulin-1

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Supramolecule #1: Potassium voltage-gated channel subfamily KQT member 1 (E150R/R22...

SupramoleculeName: Potassium voltage-gated channel subfamily KQT member 1 (E150R/R221E) in complex with calmodulin
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Xenopus laevis (African clawed frog)
Molecular weightTheoretical: 317.56 KDa

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Macromolecule #1: Potassium voltage-gated channel subfamily KQT member 1

MacromoleculeName: Potassium voltage-gated channel subfamily KQT member 1
type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Xenopus laevis (African clawed frog)
Molecular weightTheoretical: 62.375137 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MATDPPRPTI NLDPRVSIYS GRRPLLSRTN IQGRVYNFLE RPTGWKCFVY HFTVFLIVLI CLIFSVLSTI QQYNNLATET LFWMRIVLV VFFGAEYVVR LWSAGCRSKY VGVWGRLRFA RKPISVIDLI VVVASVIVLC VGSNGQVFAT SAIRGIEFLQ I LRMLHVDR ...String:
MATDPPRPTI NLDPRVSIYS GRRPLLSRTN IQGRVYNFLE RPTGWKCFVY HFTVFLIVLI CLIFSVLSTI QQYNNLATET LFWMRIVLV VFFGAEYVVR LWSAGCRSKY VGVWGRLRFA RKPISVIDLI VVVASVIVLC VGSNGQVFAT SAIRGIEFLQ I LRMLHVDR QGGTWRLLGS VVFIHRQELI TTLYIGFLGL IFSSYFVYLA EKDAIDSSGE YQFGSYADAL WWGVVTVTTI GY GDKVPQT WIGKTIASCF SVFAISFFAL PAGILGSGFA LKVQQKQRQK HFNRQIPAAA SLIQTAWRCY AAENPDSATW KIY IRKQSR NHHLMSPSPK PKKSAMVKKK KIRTERDEGS TDKMLNIPHI TYDHVADDRK NDGYSVESYE NTVRKPFGFL DPST GPFIR TSSFTDDLDM EGDTLLTPIT HISELKEHHR AAIKVIRRMQ YFVAKKKFQQ ARKPYDVRDV IEQYSQGHLN LMVRI KELQ RRLDQSLGKP SLFLSVSDKV KDKGINTIGS RLNRVEDKVT QMDHKLNLIT DMLHHLLTNQ Q

UniProtKB: Potassium voltage-gated channel subfamily KQT member 1

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Macromolecule #2: Calmodulin-1

MacromoleculeName: Calmodulin-1 / 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-1

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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

Concentration3 mg/mL
BufferpH: 7.2
Component:
ConcentrationFormulaName
150.0 mMKClpotassium chloride
20.0 mM4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
2.0 mMDithiothreitol
4.0 mMEGTA
0.03 %glyco-diosgenin
GridModel: Quantifoil R2/2 / Material: COPPER / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 25 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 98 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Name: TFS Selectris
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Number grids imaged: 4 / Number real images: 43384 / 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 / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.5 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 10095344
CTF correctionSoftware - Name: cryoSPARC (ver. 4.6.0) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionApplied symmetry - Point group: C4 (4 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.53 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.6.0) / Number images used: 95597
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.6.0)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.6.0)
FSC plot (resolution estimation)

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