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Open data
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Basic information
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Title | Structure of Xenopus KCNQ1-CaM in complex with ML277 | |||||||||
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![]() | Activator / ion channel / TRANSPORT PROTEIN-ACTIVATOR complex | |||||||||
Function / homology | ![]() regulation of gastric acid secretion / membrane repolarization / outward rectifier potassium channel activity / delayed 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 / outward rectifier potassium channel activity / delayed rectifier potassium channel activity / CaM pathway / Cam-PDE 1 activation / intestinal absorption / Sodium/Calcium exchangers / Calmodulin induced events / Reduction of cytosolic Ca++ levels / CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde / Activation of Ca-permeable Kainate Receptor / Loss of phosphorylation of MECP2 at T308 / monoatomic ion channel complex / CREB1 phosphorylation through the activation of Adenylate Cyclase / PKA activation / negative regulation of high voltage-gated calcium channel activity / CaMK IV-mediated phosphorylation of CREB / Glycogen breakdown (glycogenolysis) / positive regulation of cyclic-nucleotide phosphodiesterase activity / organelle localization by membrane tethering / negative regulation of calcium ion export across plasma membrane / CLEC7A (Dectin-1) induces NFAT activation / mitochondrion-endoplasmic reticulum membrane tethering / autophagosome membrane docking / regulation of cardiac muscle cell action potential / Activation of RAC1 downstream of NMDARs / renal absorption / positive regulation of ryanodine-sensitive calcium-release channel activity / regulation of cell communication by electrical coupling involved in cardiac conduction / Negative regulation of NMDA receptor-mediated neuronal transmission / negative regulation of peptidyl-threonine phosphorylation / Synthesis of IP3 and IP4 in the cytosol / Unblocking of NMDA receptors, glutamate binding and activation / Phase 0 - rapid depolarisation / negative regulation of ryanodine-sensitive calcium-release channel activity / protein phosphatase activator activity / voltage-gated potassium channel activity / RHO GTPases activate PAKs / : / Ion transport by P-type ATPases / inner ear development / Long-term potentiation / Uptake and function of anthrax toxins / Regulation of MECP2 expression and activity / Calcineurin activates NFAT / catalytic complex / DARPP-32 events / detection of calcium ion / regulation of cardiac muscle contraction / regulation of ryanodine-sensitive calcium-release channel activity / Smooth Muscle Contraction / cellular response to interferon-beta / RHO GTPases activate IQGAPs / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / calcium channel inhibitor activity / Protein methylation / eNOS activation / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / Activation of AMPK downstream of NMDARs / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / : / Ion homeostasis / titin binding / regulation of calcium-mediated signaling / positive regulation of protein autophosphorylation / voltage-gated potassium channel complex / sperm midpiece / calcium channel complex / phosphatidylinositol-4,5-bisphosphate binding / substantia nigra development / adenylate cyclase activator activity / Ras activation upon Ca2+ influx through NMDA receptor / regulation of heart rate / sarcomere / FCERI mediated Ca+2 mobilization / protein serine/threonine kinase activator activity / FCGR3A-mediated IL10 synthesis / VEGFR2 mediated vascular permeability / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / VEGFR2 mediated cell proliferation / regulation of cytokinesis / positive regulation of peptidyl-threonine phosphorylation / Translocation of SLC2A4 (GLUT4) to the plasma membrane / spindle microtubule / RAF activation / positive regulation of receptor signaling pathway via JAK-STAT / cytoplasmic vesicle membrane / Transcriptional activation of mitochondrial biogenesis / positive regulation of protein serine/threonine kinase activity / Stimuli-sensing channels / cellular response to type II interferon / spindle pole / response to calcium ion / RAS processing / 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 / calcium-dependent protein binding Similarity search - Function | |||||||||
Biological species | ![]() ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.9 Å | |||||||||
![]() | Willegems K / Kyriakis E | |||||||||
Funding support | 1 items
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![]() | ![]() 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 |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 167.8 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 15.3 KB 15.3 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 16.5 KB | Display | ![]() |
Images | ![]() | 97.8 KB | ||
Filedesc metadata | ![]() | 6.3 KB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 7tciMC ![]() 7tcpC C: citing same article ( M: atomic model generated by this map |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Voxel size | X=Y=Z: 0.835 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
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Sample components
-Entire : Potassium voltage-gated channel subfamily KQT member 1 in complex...
Entire | Name: Potassium voltage-gated channel subfamily KQT member 1 in complex with calmodulin and ML277 |
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Components |
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-Supramolecule #1: Potassium voltage-gated channel subfamily KQT member 1 in complex...
Supramolecule | Name: Potassium voltage-gated channel subfamily KQT member 1 in complex with calmodulin and ML277 type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2 |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 317.56 KDa |
-Macromolecule #1: Potassium voltage-gated channel subfamily KQT member 1
Macromolecule | Name: Potassium voltage-gated channel subfamily KQT member 1 type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 62.663398 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: MATDPPRPTI NLDPRVSIYS GRRPLLSRTN IQGRVYNFLE RPTGWKCFVY HFTVFLIVLI CLIFSVLSTI QQYNNLATET LFWMEIVLV VFFGAEYVVR LWSAGCRSKY VGVWGRLRFA RKPISVIDLI VVVASVIVLC VGSNGQVFAT SAIRGIRFLQ I LRMLHVDR ...String: MATDPPRPTI NLDPRVSIYS GRRPLLSRTN IQGRVYNFLE RPTGWKCFVY HFTVFLIVLI CLIFSVLSTI QQYNNLATET LFWMEIVLV VFFGAEYVVR LWSAGCRSKY VGVWGRLRFA RKPISVIDLI VVVASVIVLC VGSNGQVFAT SAIRGIRFLQ 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 QSNS UniProtKB: Potassium voltage-gated channel subfamily KQT member 1 |
-Macromolecule #2: Calmodulin-1
Macromolecule | Name: Calmodulin-1 / type: protein_or_peptide / ID: 2 / Number of copies: 4 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 16.852545 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: MADQLTEEQI AEFKEAFSLF DKDGDGTITT KELGTVMRSL GQNPTEAELQ DMINEVDADG NGTIDFPEFL TMMARKMKDT DSEEEIREA FRVFDKDGNG YISAAELRHV MTNLGEKLTD EEVDEMIREA DIDGDGQVNY EEFVQMMTAK UniProtKB: Calmodulin-1 |
-Macromolecule #3: (2R)-N-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]-1-(4-methylbenzene-...
Macromolecule | Name: (2R)-N-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]-1-(4-methylbenzene-1-sulfonyl)piperidine-2-carboxamide type: ligand / ID: 3 / Number of copies: 4 / Formula: I0S |
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Molecular weight | Theoretical: 471.592 Da |
Chemical component information | ![]() ChemComp-I0S: |
-Macromolecule #4: CALCIUM ION
Macromolecule | Name: CALCIUM ION / type: ligand / ID: 4 / Number of copies: 12 / Formula: CA |
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Molecular weight | Theoretical: 40.078 Da |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Concentration | 2 mg/mL | |||||||||||||||||||||
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Buffer | pH: 7.2 Component:
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Grid | Model: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 400 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 25 sec. / Pretreatment - Atmosphere: AIR | |||||||||||||||||||||
Vitrification | Cryogen name: ETHANE / Chamber humidity: 98 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: FEI FALCON III (4k x 4k) / Detector mode: COUNTING / Number grids imaged: 1 / Number real images: 4400 / Average electron dose: 50.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 4.8 µm / Nominal defocus min: 0.53 µm |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |