+Open data
-Basic information
Entry | Database: PDB / ID: 8uq2 | ||||||
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Title | Structure of human RyR2-S2808D in the subprimed state | ||||||
Components |
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Keywords | MEMBRANE PROTEIN / calcium channel | ||||||
Function / homology | Function and homology information junctional sarcoplasmic reticulum membrane / establishment of protein localization to endoplasmic reticulum / type B pancreatic cell apoptotic process / Purkinje myocyte to ventricular cardiac muscle cell signaling / suramin binding / regulation of SA node cell action potential / regulation of atrial cardiac muscle cell action potential / sarcoplasmic reticulum calcium ion transport / left ventricular cardiac muscle tissue morphogenesis / regulation of AV node cell action potential ...junctional sarcoplasmic reticulum membrane / establishment of protein localization to endoplasmic reticulum / type B pancreatic cell apoptotic process / Purkinje myocyte to ventricular cardiac muscle cell signaling / suramin binding / regulation of SA node cell action potential / regulation of atrial cardiac muscle cell action potential / sarcoplasmic reticulum calcium ion transport / left ventricular cardiac muscle tissue morphogenesis / regulation of AV node cell action potential / calcium-induced calcium release activity / cell communication by electrical coupling involved in cardiac conduction / regulation of ventricular cardiac muscle cell action potential / positive regulation of sequestering of calcium ion / ventricular cardiac muscle cell action potential / cyclic nucleotide binding / negative regulation of calcium-mediated signaling / embryonic heart tube morphogenesis / cardiac muscle hypertrophy / regulation of cardiac muscle contraction by calcium ion signaling / 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 / neuronal action potential propagation / response to muscle activity / insulin secretion involved in cellular response to glucose stimulus / release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / calcium ion transport into cytosol / response to caffeine / response to redox state / protein maturation by protein folding / 'de novo' protein folding / negative regulation of heart rate / positive regulation of heart rate / FK506 binding / positive regulation of axon regeneration / cellular response to caffeine / protein kinase A regulatory subunit binding / channel regulator activity / protein kinase A catalytic subunit binding / positive regulation of the force of heart contraction / intracellularly gated calcium channel activity / regulation of cardiac muscle contraction / detection of calcium ion / smooth muscle contraction / response to vitamin E / smooth endoplasmic reticulum / calcium channel inhibitor activity / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / T cell proliferation / striated muscle contraction / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / Ion homeostasis / cardiac muscle contraction / release of sequestered calcium ion into cytosol / regulation of cytosolic calcium ion concentration / sarcoplasmic reticulum membrane / calcium channel complex / cellular response to epinephrine stimulus / response to muscle stretch / regulation of heart rate / sarcoplasmic reticulum / peptidylprolyl isomerase / establishment of localization in cell / peptidyl-prolyl cis-trans isomerase activity / calcium-mediated signaling / response to hydrogen peroxide / calcium channel activity / Stimuli-sensing channels / sarcolemma / Z disc / intracellular calcium ion homeostasis / calcium ion transport / positive regulation of cytosolic calcium ion concentration / protein refolding / transmembrane transporter binding / response to hypoxia / calmodulin binding / signaling receptor binding / calcium ion binding / enzyme binding / protein-containing complex / identical protein binding / membrane / plasma membrane / cytosol / cytoplasm Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.98 Å | ||||||
Authors | Miotto, M.C. / Marks, A.R. | ||||||
Funding support | United States, 1items
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Citation | Journal: Nat Commun / Year: 2024 Title: Structural basis for ryanodine receptor type 2 leak in heart failure and arrhythmogenic disorders. Authors: Marco C Miotto / Steven Reiken / Anetta Wronska / Qi Yuan / Haikel Dridi / Yang Liu / Gunnar Weninger / Carl Tchagou / Andrew R Marks / Abstract: Heart failure, the leading cause of mortality and morbidity in the developed world, is characterized by cardiac ryanodine receptor 2 channels that are hyperphosphorylated, oxidized, and depleted of ...Heart failure, the leading cause of mortality and morbidity in the developed world, is characterized by cardiac ryanodine receptor 2 channels that are hyperphosphorylated, oxidized, and depleted of the stabilizing subunit calstabin-2. This results in a diastolic sarcoplasmic reticulum Ca leak that impairs cardiac contractility and triggers arrhythmias. Genetic mutations in ryanodine receptor 2 can also cause Ca leak, leading to arrhythmias and sudden cardiac death. Here, we solved the cryogenic electron microscopy structures of ryanodine receptor 2 variants linked either to heart failure or inherited sudden cardiac death. All are in the primed state, part way between closed and open. Binding of Rycal drugs to ryanodine receptor 2 channels reverts the primed state back towards the closed state, decreasing Ca leak, improving cardiac function, and preventing arrhythmias. We propose a structural-physiological mechanism whereby the ryanodine receptor 2 channel primed state underlies the arrhythmias in heart failure and arrhythmogenic disorders. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8uq2.cif.gz | 2.9 MB | Display | PDBx/mmCIF format |
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PDB format | pdb8uq2.ent.gz | Display | PDB format | |
PDBx/mmJSON format | 8uq2.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8uq2_validation.pdf.gz | 1.5 MB | Display | wwPDB validaton report |
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Full document | 8uq2_full_validation.pdf.gz | 1.7 MB | Display | |
Data in XML | 8uq2_validation.xml.gz | 414 KB | Display | |
Data in CIF | 8uq2_validation.cif.gz | 631.6 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/uq/8uq2 ftp://data.pdbj.org/pub/pdb/validation_reports/uq/8uq2 | HTTPS FTP |
-Related structure data
Related structure data | 42458MC 8uq3C 8uq4C 8uq5C 8uxcC 8uxeC 8uxfC 8uxgC 8uxhC 8uxiC 8uxlC 8uxmC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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-Components
#1: Protein | Mass: 565314.125 Da / Num. of mol.: 4 / Mutation: S2808D Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: RYR2 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q92736 #2: Protein | Mass: 11798.501 Da / Num. of mol.: 4 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: FKBP1B, FKBP12.6, FKBP1L, FKBP9, OTK4 / Production host: Escherichia coli (E. coli) / References: UniProt: P68106, peptidylprolyl isomerase #3: Chemical | ChemComp-ZN / #4: Chemical | ChemComp-ATP / Has ligand of interest | Y | |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
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Source (natural) |
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Source (recombinant) |
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Buffer solution | pH: 7.4 | ||||||||||||||||||||||||||||||||||||||||
Buffer component |
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Specimen | Conc.: 2.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | ||||||||||||||||||||||||||||||||||||||||
Specimen support | Grid material: GOLD / Grid type: UltrAuFoil | ||||||||||||||||||||||||||||||||||||||||
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 1200 nm / Nominal defocus min: 500 nm / Cs: 2.7 mm / C2 aperture diameter: 100 µm |
Specimen holder | Cryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Temperature (max): 100 K / Temperature (min): 80 K |
Image recording | Electron dose: 58 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) |
EM imaging optics | Energyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV |
Image scans | Sampling size: 5 µm / Width: 5760 / Height: 4092 |
-Processing
EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||||||||||||||
Symmetry | Point symmetry: C4 (4 fold cyclic) | ||||||||||||||||||||||||||||||||||||||||
3D reconstruction | Resolution: 2.98 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 191898 / Symmetry type: POINT | ||||||||||||||||||||||||||||||||||||||||
Atomic model building | PDB-ID: 7UA5 Accession code: 7UA5 / Source name: PDB / Type: experimental model | ||||||||||||||||||||||||||||||||||||||||
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