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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 / delayed rectifier potassium channel activity / outward rectifier potassium channel activity / intestinal absorption / CaM pathway / Cam-PDE 1 activation / 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 / intestinal absorption / 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 / negative regulation of high voltage-gated calcium channel activity / Glycogen breakdown (glycogenolysis) / CLEC7A (Dectin-1) induces NFAT activation / negative regulation of peptidyl-threonine phosphorylation / Activation of RAC1 downstream of NMDARs / organelle localization by membrane tethering / negative regulation of calcium ion export across plasma membrane / mitochondrion-endoplasmic reticulum membrane tethering / autophagosome membrane docking / presynaptic endocytosis / regulation of cardiac muscle cell action potential / renal absorption / positive regulation of ryanodine-sensitive calcium-release channel activity / Synthesis of IP3 and IP4 in the cytosol / regulation of cell communication by electrical coupling involved in cardiac conduction / Phase 0 - rapid depolarisation / negative regulation of ryanodine-sensitive calcium-release channel activity / Negative regulation of NMDA receptor-mediated neuronal transmission / calcineurin-mediated signaling / Unblocking of NMDA receptors, glutamate binding and activation / RHO GTPases activate PAKs / inner ear development / Ion transport by P-type ATPases / Uptake and function of anthrax toxins / Long-term potentiation / protein phosphatase activator activity / Regulation of MECP2 expression and activity / Calcineurin activates NFAT / regulation of ryanodine-sensitive calcium-release channel activity / DARPP-32 events / voltage-gated potassium channel activity / monoatomic ion channel complex / Smooth Muscle Contraction / catalytic complex / detection of calcium ion / regulation of cardiac muscle contraction / RHO GTPases activate IQGAPs / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / presynaptic cytosol / calcium channel inhibitor activity / positive regulation of protein autophosphorylation / cellular response to interferon-beta / Protein methylation / Activation of AMPK downstream of NMDARs / positive regulation of peptidyl-threonine phosphorylation / Ion homeostasis / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / eNOS activation / regulation of calcium-mediated signaling / titin binding / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / positive regulation of protein serine/threonine kinase activity / voltage-gated potassium channel complex / phosphatidylinositol-4,5-bisphosphate binding / potassium ion transmembrane transport / sperm midpiece / substantia nigra development / calcium channel complex / calyx of Held / FCERI mediated Ca+2 mobilization / Ras activation upon Ca2+ influx through NMDA receptor / FCGR3A-mediated IL10 synthesis / cytoplasmic vesicle membrane / adenylate cyclase activator activity / regulation of heart rate / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / protein serine/threonine kinase activator activity / sarcomere / VEGFR2 mediated cell proliferation / regulation of cytokinesis / VEGFR2 mediated vascular permeability / Translocation of SLC2A4 (GLUT4) to the plasma membrane / positive regulation of receptor signaling pathway via JAK-STAT / spindle microtubule / RAF activation / Transcriptional activation of mitochondrial biogenesis / cellular response to type II interferon / Stimuli-sensing channels / spindle pole / response to calcium ion / RAS processing / Signaling by RAF1 mutants / calcium-dependent protein binding / Signaling by moderate kinase activity BRAF 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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