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- EMDB-64038: structure of human KCNQ1-KCNE1-CaM complex with PIP2 -

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Basic information

Entry
Database: EMDB / ID: EMD-64038
Titlestructure of human KCNQ1-KCNE1-CaM complex with PIP2
Map data
Sample
  • Complex: Structure of human KCNQ1-KCNE1-CaM complex
    • Protein or peptide: Potassium voltage-gated channel subfamily KQT member 1
    • Protein or peptide: Calmodulin-1
    • Protein or peptide: Potassium voltage-gated channel subfamily E member 1
  • Ligand: [(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate
  • Ligand: POTASSIUM ION
KeywordsIon channels / MEMBRANE PROTEIN
Function / homology
Function and homology information


vestibular nucleus development / negative regulation of protein targeting to membrane / secretory granule organization / gastrin-induced gastric acid secretion / corticosterone secretion / voltage-gated potassium channel activity involved in atrial cardiac muscle cell action potential repolarization / basolateral part of cell / lumenal side of membrane / negative regulation of voltage-gated potassium channel activity / rhythmic behavior ...vestibular nucleus development / negative regulation of protein targeting to membrane / secretory granule organization / gastrin-induced gastric acid secretion / corticosterone secretion / voltage-gated potassium channel activity involved in atrial cardiac muscle cell action potential repolarization / basolateral part of cell / lumenal side of membrane / negative regulation of voltage-gated potassium channel activity / rhythmic behavior / stomach development / iodide transport / regulation of gastric acid secretion / voltage-gated potassium channel activity involved in cardiac muscle cell action potential repolarization / Phase 3 - rapid repolarisation / regulation of potassium ion transport / membrane repolarization during atrial cardiac muscle cell action potential / membrane repolarization during action potential / telethonin binding / Phase 2 - plateau phase / regulation of atrial cardiac muscle cell membrane repolarization / intracellular chloride ion homeostasis / membrane repolarization during ventricular cardiac muscle cell action potential / membrane repolarization during cardiac muscle cell action potential / negative regulation of delayed rectifier potassium channel activity / potassium ion export across plasma membrane / renal sodium ion absorption / voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization / atrial cardiac muscle cell action potential / membrane repolarization / auditory receptor cell development / regulation of membrane repolarization / 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 / Voltage gated Potassium channels / positive regulation of potassium ion transmembrane transport / regulation of ventricular cardiac muscle cell membrane repolarization / cardiac muscle cell action potential involved in contraction / non-motile cilium assembly / outward rectifier potassium channel activity / cardiac muscle cell contraction / regulation of potassium ion transmembrane transport / epithelial cell maturation / 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 / inner ear morphogenesis / 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 / adrenergic receptor signaling pathway / mitochondrion-endoplasmic reticulum membrane tethering / autophagosome membrane docking / negative regulation of calcium ion export across plasma membrane / regulation of cardiac muscle cell action potential / ciliary base / renal absorption / regulation of heart contraction / presynaptic endocytosis / protein kinase A regulatory subunit binding / Synthesis of IP3 and IP4 in the cytosol / protein kinase A catalytic subunit binding / regulation of cell communication by electrical coupling involved in cardiac conduction / Phase 0 - rapid depolarisation / potassium ion import across plasma membrane / 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 / regulation of heart rate by cardiac conduction / Ion transport by P-type ATPases / Uptake and function of anthrax toxins / action potential / regulation of ryanodine-sensitive calcium-release channel activity / protein phosphatase activator activity / Long-term potentiation / cochlea development / Calcineurin activates NFAT / Regulation of MECP2 expression and activity / social behavior / DARPP-32 events / voltage-gated potassium channel activity / catalytic complex / Smooth Muscle Contraction
Similarity search - Function
Potassium voltage-gated channel subfamily E member 1 / Potassium channel, voltage-dependent, beta subunit, KCNE / Slow voltage-gated potassium channel / 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 ...Potassium voltage-gated channel subfamily E member 1 / Potassium channel, voltage-dependent, beta subunit, KCNE / Slow voltage-gated potassium channel / 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 E member 1 / Potassium voltage-gated channel subfamily KQT member 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.36 Å
AuthorsHou PP / Zhang J / Wan SY / Cheng XY / Zhong L / Hu B
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Cell Res / Year: 2025
Title: Secondary structure transitions and dual PIP2 binding define cardiac KCNQ1-KCNE1 channel gating.
Authors: Ling Zhong / Xiaoqing Lin / Xinyu Cheng / Shuangyan Wan / Yaoguang Hua / Weiwei Nan / Bin Hu / Xiangjun Peng / Zihan Zhou / Qiansen Zhang / Huaiyu Yang / Frank Noé / Zhenzhen Yan / Dexiang ...Authors: Ling Zhong / Xiaoqing Lin / Xinyu Cheng / Shuangyan Wan / Yaoguang Hua / Weiwei Nan / Bin Hu / Xiangjun Peng / Zihan Zhou / Qiansen Zhang / Huaiyu Yang / Frank Noé / Zhenzhen Yan / Dexiang Jiang / Hangyu Zhang / Fengjiao Liu / Chenxin Xiao / Zhuo Zhou / Yimin Mou / Haijie Yu / Lijuan Ma / Chen Huang / Vincent Kam Wai Wong / Sookja Kim Chung / Bing Shen / Zhi-Hong Jiang / Erwin Neher / Wandi Zhu / Jin Zhang / Panpan Hou /
Abstract: The KCNQ1 + KCNE1 potassium channel complex produces the slow delayed rectifier current (I) critical for cardiac repolarization. Loss-of-function mutations in KCNQ1 and KCNE1 cause long QT ...The KCNQ1 + KCNE1 potassium channel complex produces the slow delayed rectifier current (I) critical for cardiac repolarization. Loss-of-function mutations in KCNQ1 and KCNE1 cause long QT syndrome (LQTS) types 1 and 5 (LQT1/LQT5), accounting for over one-third of clinical LQTS cases. Despite prior structural work on KCNQ1 and KCNQ1 + KCNE3, the structural basis of KCNQ1 + KCNE1 remains unresolved. Using cryo-electron microscopy and electrophysiology, we determined high-resolution (2.5-3.4 Å) structures of human KCNQ1, and KCNQ1 + KCNE1 in both closed and open states. KCNE1 occupies a pivotal position at the interface of three KCNQ1 subunits, inducing six helix-to-loop transitions in KCNQ1 transmembrane segments. Three of them occur at both ends of the S4-S5 linker, maintaining a loop conformation during I gating, while the other three, in S6 and helix A, undergo dynamic helix-loop transitions during I gating. These structural rearrangements: (1) stabilize the closed pore and the conformation of the intermediate state voltage-sensing domain, thereby determining channel gating, ion permeation, and single-channel conductance; (2) enable a dual-PIP2 modulation mechanism, where one PIP2 occupies the canonical site, while the second PIP2 bridges the S4-S5 linker, KCNE1, and the adjacent S6', stabilizing channel opening; (3) create a fenestration capable of binding compounds specific for KCNQ1 + KCNE1 (e.g., AC-1). Together, these findings reveal a previously unrecognized large-scale secondary structural transition during ion channel gating that fine-tunes I function and provides a foundation for developing targeted LQTS therapy.
History
DepositionApr 3, 2025-
Header (metadata) releaseNov 5, 2025-
Map releaseNov 5, 2025-
UpdateNov 5, 2025-
Current statusNov 5, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_64038.png

Downloads & links

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Map

FileDownload / File: emd_64038.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
0.96 Å/pix.
x 400 pix.
= 384. Å		0.96 Å/pix.
x 400 pix.
= 384. Å		0.96 Å/pix.
x 400 pix.
= 384. Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.96 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.12
Minimum - Maximum-0.8577062 - 1.4639704
Average (Standard dev.)0.0006114019 (±0.017598014)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 384.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_64038_half_map_1.map
Projections & Slices
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Histogram (log scale)

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Half map: #1

Fileemd_64038_half_map_2.map
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Sample components

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Entire : Structure of human KCNQ1-KCNE1-CaM complex

EntireName: Structure of human KCNQ1-KCNE1-CaM complex
Components
  • Complex: Structure of human KCNQ1-KCNE1-CaM complex
    • Protein or peptide: Potassium voltage-gated channel subfamily KQT member 1
    • Protein or peptide: Calmodulin-1
    • Protein or peptide: Potassium voltage-gated channel subfamily E member 1
  • Ligand: [(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate
  • Ligand: POTASSIUM ION

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Supramolecule #1: Structure of human KCNQ1-KCNE1-CaM complex

SupramoleculeName: Structure of human KCNQ1-KCNE1-CaM complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
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 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 74.800492 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAAASSPPRA ERKRWGWGRL PGARRGSAGL AKKCPFSLEL AEGGPAGGAL YAPIAPGAPG PAPPASPAAP AAPPVASDLG PRPPVSLDP RVSIYSTRRP VLARTHVQGR VYNFLERPTG WKCFVYHFAV FLIVLVCLIF SVLSTIEQYA ALATGTLFWM E IVLVVFFG ...String:
MAAASSPPRA ERKRWGWGRL PGARRGSAGL AKKCPFSLEL AEGGPAGGAL YAPIAPGAPG PAPPASPAAP AAPPVASDLG PRPPVSLDP RVSIYSTRRP VLARTHVQGR VYNFLERPTG WKCFVYHFAV FLIVLVCLIF SVLSTIEQYA ALATGTLFWM E IVLVVFFG TEYVVRLWSA GCRSKYVGLW GRLRFARKPI SIIDLIVVVA SMVVLCVGSK GQVFATSAIR GIRFLQILRM LH VDRQGGT WRLLGSVVFI HRQELITTLY IGFLGLIFSS YFVYLAEKDA VNESGRVEFG SYADALWWGV VTVTTIGYGD KVP QTWVGK TIASCFSVFA ISFFALPAGI LGSGFALKVQ QKQRQKHFNR QIPAAASLIQ TAWRCYAAEN PDSSTWKIYI RKAP RSHTL LSPSPKPKKS VVVKKKKFKL DKDNGVTPGE KMLTVPHITC DPPEERRLDH FSVDGYDSSV RKSPTLLEVS MPHFM RTNS FAEDLDLEGE TLLTPITHIS QLREHHRATI KVIRRMQYFV AKKKFQQARK PYDVRDVIEQ YSQGHLNLMV RIKELQ RRL DQSIGKPSLF ISVSEKSKDR GSNTIGARLN RVEDKVTQLD QRLALITDML HQLLSLHGGS TPGSGGPPRE GGAHITQ PC GSGGSVDPEL FLPSNTLPTY EQLTVPRRGP DEGS

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: Potassium voltage-gated channel subfamily E member 1

MacromoleculeName: Potassium voltage-gated channel subfamily E member 1 / type: protein_or_peptide / ID: 3 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 3.404093 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
DGKLEALYVL MVLGFFGFFT LGIMLSYIRS

UniProtKB: Potassium voltage-gated channel subfamily E member 1

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Macromolecule #4: [(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(o...

MacromoleculeName: [(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate
type: ligand / ID: 4 / Number of copies: 8 / Formula: PIO
Molecular weightTheoretical: 746.566 Da
Chemical component information

ChemComp-PIO:
[(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate

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Macromolecule #5: POTASSIUM ION

MacromoleculeName: POTASSIUM ION / type: ligand / ID: 5 / 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

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TECNAI SPIRIT
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 50.73 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: 1.0 µm
Experimental equipment
Model: Tecnai Spirit / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.36 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 168370
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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