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- EMDB-26414: Structure of PKA phosphorylated human RyR2-R2474S in the open sta... -
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Open data
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Basic information
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Title | Structure of PKA phosphorylated human RyR2-R2474S in the open state in the presence of Calmodulin | |||||||||
![]() | Composite map of the Structure of PKA phosphorylated human RyR2-R2474S in the open state in the presence of Calmodulin. | |||||||||
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Function / homology | ![]() junctional sarcoplasmic reticulum membrane / suramin binding / establishment of protein localization to endoplasmic reticulum / type B pancreatic cell apoptotic process / Purkinje myocyte to ventricular cardiac muscle cell signaling / regulation of SA node cell action potential / regulation of atrial cardiac muscle cell action potential / left ventricular cardiac muscle tissue morphogenesis / regulation of AV node cell action potential / positive regulation of ATPase-coupled calcium transmembrane transporter activity ...junctional sarcoplasmic reticulum membrane / suramin binding / establishment of protein localization to endoplasmic reticulum / type B pancreatic cell apoptotic process / Purkinje myocyte to ventricular cardiac muscle cell signaling / regulation of SA node cell action potential / regulation of atrial cardiac muscle cell action potential / left ventricular cardiac muscle tissue morphogenesis / regulation of AV node cell action potential / positive regulation of ATPase-coupled calcium transmembrane transporter activity / calcium-induced calcium release activity / sarcoplasmic reticulum calcium ion transport / ventricular cardiac muscle cell action potential / regulation of ventricular cardiac muscle cell action potential / positive regulation of sequestering of calcium ion / cyclic nucleotide binding / embryonic heart tube morphogenesis / cardiac muscle hypertrophy / negative regulation of insulin secretion involved in cellular response to glucose stimulus / negative regulation of release of sequestered calcium ion into cytosol / ryanodine-sensitive calcium-release channel activity / regulation of cardiac muscle contraction by calcium ion signaling / neuronal action potential propagation / insulin secretion involved in cellular response to glucose stimulus / release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / CaM pathway / Cam-PDE 1 activation / response to muscle activity / calcium ion transport into cytosol / Sodium/Calcium exchangers / response to caffeine / cell communication by electrical coupling involved in cardiac conduction / Calmodulin induced events / response to redox state / protein maturation by protein folding / Reduction of cytosolic Ca++ levels / CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde / Activation of Ca-permeable Kainate Receptor / 'de novo' protein folding / Loss of phosphorylation of MECP2 at T308 / 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 / negative regulation of heart rate / organelle localization by membrane tethering / negative regulation of calcium ion export across plasma membrane / CLEC7A (Dectin-1) induces NFAT activation / regulation of cardiac muscle cell action potential / mitochondrion-endoplasmic reticulum membrane tethering / autophagosome membrane docking / negative regulation of phosphoprotein phosphatase activity / Activation of RAC1 downstream of NMDARs / positive regulation of heart rate / FK506 binding / positive regulation of ryanodine-sensitive calcium-release channel activity / positive regulation of axon regeneration / regulation of cell communication by electrical coupling involved in cardiac conduction / Negative regulation of NMDA receptor-mediated neuronal transmission / cellular response to caffeine / 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 / protein kinase A regulatory subunit binding / intracellularly gated calcium channel activity / protein phosphatase activator activity / protein kinase A catalytic subunit binding / RHO GTPases activate PAKs / positive regulation of the force of heart contraction / positive regulation of phosphoprotein phosphatase activity / Ion transport by P-type ATPases / Long-term potentiation / Uptake and function of anthrax toxins / : / Calcineurin activates NFAT / Regulation of MECP2 expression and activity / catalytic complex / DARPP-32 events / detection of calcium ion / smooth muscle contraction / regulation of cardiac muscle contraction / smooth endoplasmic reticulum / negative regulation of ryanodine-sensitive calcium-release channel activity / Smooth Muscle Contraction / response to vitamin E / calcium channel inhibitor activity / RHO GTPases activate IQGAPs / cellular response to interferon-beta / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / Protein methylation / protein peptidyl-prolyl isomerization / eNOS activation / T cell proliferation / striated muscle contraction / Activation of AMPK downstream of NMDARs / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / cardiac muscle contraction Similarity search - 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Biological species | ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.93 Å | |||||||||
![]() | Miotto MC / Marks AR | |||||||||
Funding support | ![]()
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![]() | ![]() Title: Structural analyses of human ryanodine receptor type 2 channels reveal the mechanisms for sudden cardiac death and treatment. Authors: Marco C Miotto / Gunnar Weninger / Haikel Dridi / Qi Yuan / Yang Liu / Anetta Wronska / Zephan Melville / Leah Sittenfeld / Steven Reiken / Andrew R Marks / ![]() Abstract: Ryanodine receptor type 2 (RyR2) mutations have been linked to an inherited form of exercise-induced sudden cardiac death called catecholaminergic polymorphic ventricular tachycardia (CPVT). CPVT ...Ryanodine receptor type 2 (RyR2) mutations have been linked to an inherited form of exercise-induced sudden cardiac death called catecholaminergic polymorphic ventricular tachycardia (CPVT). CPVT results from stress-induced sarcoplasmic reticular Ca leak via the mutant RyR2 channels during diastole. We present atomic models of human wild-type (WT) RyR2 and the CPVT mutant RyR2-R2474S determined by cryo-electron microscopy with overall resolutions in the range of 2.6 to 3.6 Å, and reaching local resolutions of 2.25 Å, unprecedented for RyR2 channels. Under nonactivating conditions, the RyR2-R2474S channel is in a "primed" state between the closed and open states of WT RyR2, rendering it more sensitive to activation that results in stress-induced Ca leak. The Rycal drug ARM210 binds to RyR2-R2474S, reverting the primed state toward the closed state. Together, these studies provide a mechanism for CPVT and for the therapeutic actions of ARM210. | |||||||||
History |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 244.8 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 23.6 KB 23.6 KB | Display Display | ![]() |
Images | ![]() | 138.7 KB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 420.5 KB | Display | ![]() |
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Full document | ![]() | 420.1 KB | Display | |
Data in XML | ![]() | 8 KB | Display | |
Data in CIF | ![]() | 9.2 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 7ua4MC ![]() 7u9qC ![]() 7u9rC ![]() 7u9tC ![]() 7u9xC ![]() 7u9zC ![]() 7ua1C ![]() 7ua3C ![]() 7ua5C ![]() 7ua9C M: atomic model generated by this map C: citing same article ( |
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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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Annotation | Composite map of the Structure of PKA phosphorylated human RyR2-R2474S in the open state in the presence of Calmodulin. | ||||||||||||||||||||
Voxel size | X=Y=Z: 0.832 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 : Complex of RyR2-R2474S, Calstabin-2, and Calmodulin
+Supramolecule #1: Complex of RyR2-R2474S, Calstabin-2, and Calmodulin
+Supramolecule #2: Ryanodine receptor 2
+Supramolecule #3: Peptidyl-prolyl cis-trans isomerase FKBP1B (E.C.5.2.1.8), Calmodulin-1
+Macromolecule #1: Ryanodine receptor 2
+Macromolecule #2: Peptidyl-prolyl cis-trans isomerase FKBP1B
+Macromolecule #3: Calmodulin-1
+Macromolecule #4: ZINC ION
+Macromolecule #5: ADENOSINE-5'-TRIPHOSPHATE
+Macromolecule #6: CALCIUM ION
+Macromolecule #7: XANTHINE
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Concentration | 2.2 mg/mL | |||||||||||||||||||||||||||||||||
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Buffer | pH: 7.4 Component:
Details: Xanthine was made fresh to avoid aggregation. Xanthine stock solution was 10 mM in NaOH 0.5 N. | |||||||||||||||||||||||||||||||||
Grid | Model: UltrAuFoil R0.6/1 / Material: GOLD / Pretreatment - Type: GLOW DISCHARGE | |||||||||||||||||||||||||||||||||
Vitrification | Cryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV | |||||||||||||||||||||||||||||||||
Details | 40 uM of Calmodulin was added to the final sample. |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Digitization - Dimensions - Width: 5760 pixel / Digitization - Dimensions - Height: 4092 pixel / Average electron dose: 58.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.2 µm / Nominal defocus min: 0.4 µm |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |