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- EMDB-76332: structure of human KCNQ1-CaM-PIP2 intermediate state -

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Basic information

Entry
Database: EMDB / ID: EMD-76332
Titlestructure of human KCNQ1-CaM-PIP2 intermediate state
Map data
Sample
  • Complex: KCNQ1-CaM-PIP2
    • Protein or peptide: Potassium voltage-gated channel subfamily KQT member 1
    • Protein or peptide: Calmodulin-1
  • 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: CALCIUM ION
KeywordsKCNQ1 / intermediate state / PIP2 / MEMBRANE PROTEIN
Function / homology
Function and homology information


gastrin-induced gastric acid secretion / corticosterone secretion / voltage-gated potassium channel activity involved in atrial cardiac muscle cell action potential repolarization / negative regulation of voltage-gated potassium channel activity / basolateral part of cell / lumenal side of membrane / negative regulation of delayed rectifier potassium channel activity / rhythmic behavior / stomach development / regulation of gastric acid secretion ...gastrin-induced gastric acid secretion / corticosterone secretion / voltage-gated potassium channel activity involved in atrial cardiac muscle cell action potential repolarization / negative regulation of voltage-gated potassium channel activity / basolateral part of cell / lumenal side of membrane / negative regulation of delayed rectifier potassium channel activity / rhythmic behavior / stomach development / regulation of gastric acid secretion / voltage-gated potassium channel activity involved in cardiac muscle cell action potential repolarization / Phase 3 - rapid repolarisation / membrane repolarization during action potential / membrane repolarization during atrial cardiac muscle cell action potential / Phase 2 - plateau phase / iodide transport / regulation of atrial cardiac muscle cell membrane repolarization / membrane repolarization during ventricular cardiac muscle cell action potential / intracellular chloride ion homeostasis / potassium ion export across plasma membrane / membrane repolarization during cardiac muscle cell action potential / voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization / atrial cardiac muscle cell action potential / regulation of membrane repolarization / renal sodium ion absorption / auditory receptor cell development / protein phosphatase 1 binding / detection of mechanical stimulus involved in sensory perception of sound / delayed rectifier potassium channel activity / ventricular cardiac muscle cell action potential / potassium ion homeostasis / regulation of ventricular cardiac muscle cell membrane repolarization / positive regulation of potassium ion transmembrane transport / Voltage gated Potassium channels / non-motile cilium assembly / outward rectifier potassium channel activity / intestinal absorption / CaM pathway / Cam-PDE 1 activation / Sodium/Calcium exchangers / inner ear morphogenesis / Calmodulin induced events / cardiac muscle cell contraction / 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 / adrenergic receptor signaling pathway / negative regulation of high voltage-gated calcium channel activity / PKA activation / CaMK IV-mediated phosphorylation of CREB / Glycogen breakdown (glycogenolysis) / CLEC7A (Dectin-1) induces NFAT activation / renal absorption / negative regulation of ryanodine-sensitive calcium-release channel activity / organelle localization by membrane tethering / Activation of RAC1 downstream of NMDARs / : / autophagosome membrane docking / protein kinase A regulatory subunit binding / ciliary base / protein kinase A catalytic subunit binding / negative regulation of calcium ion export across plasma membrane / regulation of ryanodine-sensitive calcium-release channel activity / regulation of cardiac muscle cell action potential / regulation of heart contraction / presynaptic endocytosis / inner ear development / Synthesis of IP3 and IP4 in the cytosol / Phase 0 - rapid depolarisation / potassium ion import across plasma membrane / Negative regulation of NMDA receptor-mediated neuronal transmission / Unblocking of NMDA receptors, glutamate binding and activation / RHO GTPases activate PAKs / calcineurin-mediated signaling / regulation of heart rate by cardiac conduction / regulation of cell communication by electrical coupling involved in cardiac conduction / monoatomic ion channel complex / Ion transport by P-type ATPases / Uptake and function of anthrax toxins / cochlea development / protein phosphatase activator activity / Long-term potentiation / Calcineurin activates NFAT / action potential / Regulation of MECP2 expression and activity / DARPP-32 events / Smooth Muscle Contraction / voltage-gated potassium channel activity / detection of calcium ion / social behavior / regulation of cardiac muscle contraction / catalytic complex / positive regulation of heart rate / RHO GTPases activate IQGAPs / transport vesicle / calcium channel inhibitor activity / presynaptic cytosol / Activation of AMPK downstream of NMDARs
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 / EF-hand domain pair / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
Calmodulin-1 / Potassium voltage-gated channel subfamily KQT member 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.47 Å
AuthorsCui C / Kermani A / Sun J
Funding support United States, Singapore, 6 items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)R01HL155398 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)R01HL166628 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)1R35GM136409 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)2R35GM136409 United States
Ministry of Education (MoE, Singapore)A-8002958-00-00 Singapore
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)R00HL143037 United States
CitationJournal: Res Sq / Year: 2025
Title: PIP activation of the cardiac I potassium channel.
Authors: Jianmin Cui / Lu Zhao / Xianjin Xu / Chenxi Cui / Rui Duan / Ali Kermani / Jingyi Shi / Lu Han / Ji Sun / Xiaoqin Zou /
Abstract: The I channel complex, composed of the voltage-gated potassium channel KCNQ1 and its regulatory subunit KCNE1, is essential for the termination of cardiac action potentials. The function of KCNQ1 and ...The I channel complex, composed of the voltage-gated potassium channel KCNQ1 and its regulatory subunit KCNE1, is essential for the termination of cardiac action potentials. The function of KCNQ1 and I requires PIP, and its depletion abolishes channel opening. Previous studies revealed that KCNQ1 adopts both bent and straight conformations and can bind two PIP molecules: one adjacent to VSD (V-PIP), and the other at the VSD-pore interface (C-PIP). Here we show that the two PIP perform essential yet distinct roles: V-PIP enables the bent-to-straight transition, whereas C-PIP mediates VSD-pore coupling and stabilizes the straight conformation. Structure-function analysis and molecular dynamic simulations show that VSD activation elevates the V-PIP site and weakens the CaM-VSD interaction, permitting the conformational shift from the bent, intermediate open (IO) state associated with KCNQ1 to the straight, I-exclusive activated open (AO) state, which is further stabilized by C-PIP. Leveraging this mechanism, we developed a compound CA1, which selectively targets the V-PIP site and modulates I channel activity without affecting KCNQ1, offering a novel and promising conceptional path for specific and safe antiarrhythmic therapeutics.
History
DepositionMar 28, 2026-
Header (metadata) releaseMay 6, 2026-
Map releaseMay 6, 2026-
UpdateJun 17, 2026-
Current statusJun 17, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_76332.png

Downloads & links

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Map

FileDownload / File: emd_76332.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.4 Å/pix.
x 256 pix.
= 358.4 Å		1.4 Å/pix.
x 256 pix.
= 358.4 Å		1.4 Å/pix.
x 256 pix.
= 358.4 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.4 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.7
Minimum - Maximum-3.5825925 - 6.278618
Average (Standard dev.)0.002649269 (±0.087360345)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 358.4 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_76332_half_map_1.map
Projections & Slices
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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_76332_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : KCNQ1-CaM-PIP2

EntireName: KCNQ1-CaM-PIP2
Components
  • Complex: KCNQ1-CaM-PIP2
    • Protein or peptide: Potassium voltage-gated channel subfamily KQT member 1
    • Protein or peptide: Calmodulin-1
  • 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: CALCIUM ION

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Supramolecule #1: KCNQ1-CaM-PIP2

SupramoleculeName: KCNQ1-CaM-PIP2 / 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 1

MacromoleculeName: Potassium voltage-gated channel subfamily KQT member 1
type: protein_or_peptide / ID: 1 / Details: 76-620 reserved / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 61.945066 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: ASDLGPRPPV SLDPRVSIYS TRRPVLARTH VQGRVYNFLE RPTGWKCFVY HFAVFLIVLV CLIFSVLSTC EQYAALATGT LFWMRIVLV VFFGTEYVVR LWSAGCRSKY VGLWGRLRFA RKPISIIDLI VVVASMVVLC VGSKGQVFAT SAIRGIEFLQ I LRMLHVDR ...String:
ASDLGPRPPV SLDPRVSIYS TRRPVLARTH VQGRVYNFLE RPTGWKCFVY HFAVFLIVLV CLIFSVLSTC EQYAALATGT LFWMRIVLV VFFGTEYVVR LWSAGCRSKY VGLWGRLRFA RKPISIIDLI VVVASMVVLC VGSKGQVFAT SAIRGIEFLQ I LRMLHVDR QGGTWRLLGS VVFIHRQELI TTLYIGFLGL IFSSYFVYLA EKDAVNESGR VEFGSYADAL WWGVVTVTTI GY GDKVPQT WVGKTIASCF SVFAISFFAL PAGILGSGFA LKVQQKQRQK HFNRQIPAAA SLIQTAWRCY AAENPDSSTW KIY IRKAPR SHTLLSPSPK PKKSVVVKKK KFKLDKDNGV TPGEKMLTVP HITCDPPEER RLDHFSVDGY DSSVRKSPTL LEVS MPHFM RTNSFAEDLD LEGETLLTPI THISQLREHH RATIKVIRRM QYFVAKKKFQ QARKPYDVRD VIEQYSQGHL NLMVR IKEL QRRLDQSIGK PSLFISVSEK SKDRGSNTIG ARLNRVEDKV TQLDQRLALI TDMLHQLLSL H

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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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: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 4 / Number of copies: 8 / Formula: CA
Molecular weightTheoretical: 40.078 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

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
SoftwareName: EPU
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 52.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.47 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 161967
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: ANGULAR RECONSTITUTION

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