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- PDB-7tcp: Structure of Xenopus KCNQ1-CaM -

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Basic information

Entry
Database: PDB / ID: 7tcp
TitleStructure of Xenopus KCNQ1-CaM
Components
  • Calmodulin-1
  • Potassium voltage-gated channel subfamily KQT member 1
KeywordsTRANSPORT PROTEIN / ion channel
Function / homology
Function and homology information


regulation of gastric acid secretion / membrane repolarization / intestinal absorption / delayed rectifier potassium channel activity / outward rectifier potassium channel activity / CaM pathway / Cam-PDE 1 activation / Sodium/Calcium exchangers / Calmodulin induced events / Reduction of cytosolic Ca++ levels ...regulation of gastric acid secretion / membrane repolarization / intestinal absorption / delayed rectifier potassium channel activity / outward rectifier potassium channel activity / CaM pathway / Cam-PDE 1 activation / 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 / PKA activation / CaMK IV-mediated phosphorylation of CREB / inner ear development / CASP4 inflammasome assembly / Glycogen breakdown (glycogenolysis) / monoatomic ion channel complex / renal absorption / negative regulation of ryanodine-sensitive calcium-release channel activity / Activation of RAC1 downstream of NMDARs / organelle localization by membrane tethering / CLEC7A (Dectin-1) induces NFAT activation / : / negative regulation of high voltage-gated calcium channel activity / autophagosome membrane docking / negative regulation of calcium ion export across plasma membrane / regulation of cardiac muscle cell action potential / presynaptic endocytosis / Synthesis of IP3 and IP4 in the cytosol / Phase 0 - rapid depolarisation / Negative regulation of NMDA receptor-mediated neuronal transmission / Unblocking of NMDA receptors, glutamate binding and activation / calcineurin-mediated signaling / RHO GTPases activate PAKs / regulation of cell communication by electrical coupling involved in cardiac conduction / Uptake and function of anthrax toxins / Ion transport by P-type ATPases / protein phosphatase activator activity / Long-term potentiation / Calcineurin activates NFAT / regulation of ryanodine-sensitive calcium-release channel activity / catalytic complex / Regulation of MECP2 expression and activity / DARPP-32 events / Smooth Muscle Contraction / detection of calcium ion / voltage-gated potassium channel activity / regulation of cardiac muscle contraction / cellular response to interferon-beta / RHO GTPases activate IQGAPs / calcium channel inhibitor activity / presynaptic cytosol / eNOS activation / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / Activation of AMPK downstream of NMDARs / Ion homeostasis / regulation of heart rate / Protein methylation / titin binding / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / phosphatidylinositol-4,5-bisphosphate binding / voltage-gated potassium channel complex / calcium channel complex / FCERI mediated Ca+2 mobilization / substantia nigra development / FCGR3A-mediated IL10 synthesis / potassium ion transmembrane transport / protein serine/threonine kinase activator activity / sperm midpiece / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / cytoplasmic vesicle membrane / calyx of Held / positive regulation of receptor signaling pathway via JAK-STAT / Ras activation upon Ca2+ influx through NMDA receptor / adenylate cyclase activator activity / regulation of cytokinesis / VEGFR2 mediated cell proliferation / VEGFR2 mediated vascular permeability / spindle microtubule / sarcomere / Translocation of SLC2A4 (GLUT4) to the plasma membrane / calcium channel regulator activity / myelin sheath / cellular response to type II interferon / Transcriptional activation of mitochondrial biogenesis / long-term synaptic potentiation / Enterobacterial factors antagonize host defense / response to calcium ion / RAF activation / Stimuli-sensing channels / spindle pole / calcium-dependent protein binding / Signaling by RAF1 mutants / 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 / Recoverin; domain 1 / : / EF-hand domain pair / EF-hand, calcium binding motif ...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 / Recoverin; domain 1 / : / 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 / Orthogonal Bundle / Mainly Alpha
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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.84 Å
AuthorsWillegems, K. / Kyriakis, E. / Van Petegem, F. / Eldstrom, J. / Fedida, D.
Funding support Canada, 1items
OrganizationGrant numberCountry
Canadian Institutes of Health Research (CIHR) Canada
CitationJournal: Nat Commun / Year: 2022
Title: Structural and electrophysiological basis for the modulation of KCNQ1 channel currents by ML277.
Authors: Katrien Willegems / Jodene Eldstrom / Efthimios Kyriakis / Fariba Ataei / Harutyun Sahakyan / Ying Dou / Sophia Russo / Filip Van Petegem / David Fedida /
Abstract: The KCNQ1 ion channel plays critical physiological roles in electrical excitability and K recycling in organs including the heart, brain, and gut. Loss of function is relatively common and can cause ...The KCNQ1 ion channel plays critical physiological roles in electrical excitability and K recycling in organs including the heart, brain, and gut. Loss of function is relatively common and can cause sudden arrhythmic death, sudden infant death, epilepsy and deafness. Here, we report cryogenic electron microscopic (cryo-EM) structures of Xenopus KCNQ1 bound to Ca/Calmodulin, with and without the KCNQ1 channel activator, ML277. A single binding site for ML277 was identified, localized to a pocket lined by the S4-S5 linker, S5 and S6 helices of two separate subunits. Several pocket residues are not conserved in other KCNQ isoforms, explaining specificity. MD simulations and point mutations support this binding location for ML277 in open and closed channels and reveal that prevention of inactivation is an important component of the activator effect. Our work provides direction for therapeutic intervention targeting KCNQ1 loss of function pathologies including long QT interval syndrome and seizures.
History
DepositionDec 27, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 6, 2022Provider: repository / Type: Initial release
Revision 1.0Jul 6, 2022Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jul 6, 2022Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jul 6, 2022Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jul 6, 2022Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0Jul 6, 2022Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jul 6, 2022Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jul 6, 2022Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Feb 28, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond
Revision 1.2May 21, 2025Group: Data collection / Structure summary / Category: em_admin / em_software / pdbx_entry_details
Item: _em_admin.last_update / _em_software.name / _pdbx_entry_details.has_protein_modification
Revision 1.1May 21, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Potassium voltage-gated channel subfamily KQT member 1
B: Calmodulin-1
E: Potassium voltage-gated channel subfamily KQT member 1
F: Calmodulin-1
G: Potassium voltage-gated channel subfamily KQT member 1
H: Calmodulin-1
C: Potassium voltage-gated channel subfamily KQT member 1
D: Calmodulin-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)318,54520
Polymers318,0648
Non-polymers48112
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Potassium voltage-gated channel subfamily KQT member 1 / IKs producing slow voltage-gated potassium channel subunit alpha xKvLQT1 / KQT-like 1 / Voltage- ...IKs producing slow voltage-gated potassium channel subunit alpha xKvLQT1 / KQT-like 1 / Voltage-gated potassium channel subunit Kv7.1 / KCNQ1


Mass: 62663.398 Da / Num. of mol.: 4 / Fragment: UNP residues 67-610
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Xenopus laevis (African clawed frog) / Gene: kcnq1, kvlqt1 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: P70057
#2: Protein
Calmodulin-1


Mass: 16852.545 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CALM1, CALM, CAM, CAM1 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: P0DP23
#3: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: Ca
Has ligand of interestN
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Potassium voltage-gated channel subfamily KQT member 1 in complex with calmodulin
Type: COMPLEX / Entity ID: #1-#2 / Source: MULTIPLE SOURCES
Molecular weightValue: 0.31756 MDa / Experimental value: NO
Source (natural)Organism: Xenopus laevis (African clawed frog)
Source (recombinant)Organism: Homo sapiens (human) / Cell: HEK293
Buffer solutionpH: 7.2
Buffer component
IDConc.NameFormulaBuffer-ID
1150 mMpotassium chlorideKCl1
220 mM4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid1
30.5 mMCalcium chlorideCaCl21
42 mMDithiothreitol1
50.05 %n-Dodecyl-B-D-maltoside1
60.005 %Cholesteryl hemisuccinate1
SpecimenConc.: 2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 400 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 98 % / Chamber temperature: 277.15 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 4900 nm / Nominal defocus min: 360 nm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 50 e/Å2 / Detector mode: COUNTING / Film or detector model: FEI FALCON IV (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 19997

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Processing

SoftwareName: PHENIX / Version: 1.19.2_4158: / Classification: refinement
EM software
IDNameVersionCategory
2EPUimage acquisition
4CTFFIND4CTF correction
9PHENIXmodel refinement
10cryoSPARC3.3.1initial Euler assignment
11cryoSPARC3.3.1final Euler assignment
13cryoSPARC3.3.13D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 1830000
SymmetryPoint symmetry: C4 (4 fold cyclic)
3D reconstructionResolution: 3.84 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 71241 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00215304
ELECTRON MICROSCOPYf_angle_d0.36320720
ELECTRON MICROSCOPYf_dihedral_angle_d9.5695372
ELECTRON MICROSCOPYf_chiral_restr0.0352340
ELECTRON MICROSCOPYf_plane_restr0.0022604

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