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- PDB-9c1f: Mink RyR3 in open conformation bound to Ca2+/ATP/caffeine -

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Basic information

Entry
Database: PDB / ID: 9c1f
TitleMink RyR3 in open conformation bound to Ca2+/ATP/caffeine
Components
  • Peptidyl-prolyl cis-trans isomerase FKBP1B
  • Ryanodine receptor 3
KeywordsMEMBRANE PROTEIN / RyR3 / Ryanodine Receptor / calcium channel / ion channel
Function / homology
Function and homology information


positive regulation of sequestering of calcium ion / cyclic nucleotide binding / negative regulation of calcium-mediated signaling / negative regulation of insulin secretion involved in cellular response to glucose stimulus / negative regulation of release of sequestered calcium ion into cytosol / neuronal action potential propagation / insulin secretion involved in cellular response to glucose stimulus / ryanodine-sensitive calcium-release channel activity / release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / response to redox state ...positive regulation of sequestering of calcium ion / cyclic nucleotide binding / negative regulation of calcium-mediated signaling / negative regulation of insulin secretion involved in cellular response to glucose stimulus / negative regulation of release of sequestered calcium ion into cytosol / neuronal action potential propagation / insulin secretion involved in cellular response to glucose stimulus / ryanodine-sensitive calcium-release channel activity / release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / response to redox state / 'de novo' protein folding / negative regulation of heart rate / FK506 binding / positive regulation of axon regeneration / smooth muscle contraction / response to vitamin E / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / smooth endoplasmic reticulum / calcium channel inhibitor activity / striated muscle contraction / T cell proliferation / Ion homeostasis / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / release of sequestered calcium ion into cytosol / sarcoplasmic reticulum membrane / calcium channel regulator activity / calcium channel complex / protein maturation / peptidyl-prolyl cis-trans isomerase activity / RNA polymerase II CTD heptapeptide repeat P3 isomerase activity / RNA polymerase II CTD heptapeptide repeat P6 isomerase activity / peptidylprolyl isomerase / calcium-mediated signaling / sarcolemma / response to hydrogen peroxide / Stimuli-sensing channels / Z disc / intracellular calcium ion homeostasis / positive regulation of cytosolic calcium ion concentration / protein refolding / transmembrane transporter binding / calmodulin binding / signaling receptor binding / calcium ion binding / membrane / cytoplasm
Similarity search - Function
Ryanodine receptor, SPRY domain 2 / : / Ryanodine receptor junctional solenoid repeat / Ryanodine Receptor TM 4-6 / Ryanodine receptor / Ryanodine receptor, SPRY domain 1 / Ryanodine receptor, SPRY domain 3 / Ryanodine Receptor TM 4-6 / Ryanodine receptor Ryr / RyR domain ...Ryanodine receptor, SPRY domain 2 / : / Ryanodine receptor junctional solenoid repeat / Ryanodine Receptor TM 4-6 / Ryanodine receptor / Ryanodine receptor, SPRY domain 1 / Ryanodine receptor, SPRY domain 3 / Ryanodine Receptor TM 4-6 / Ryanodine receptor Ryr / RyR domain / : / RyR/IP3 receptor binding core, RIH domain superfamily / RyR/IP3R Homology associated domain / Inositol 1,4,5-trisphosphate/ryanodine receptor / RIH domain / RyR and IP3R Homology associated / Inositol 1,4,5-trisphosphate/ryanodine receptor / RIH domain / : / MIR motif / MIR domain / MIR domain profile. / Domain in ryanodine and inositol trisphosphate receptors and protein O-mannosyltransferases / Mir domain superfamily / SPRY domain / B30.2/SPRY domain / B30.2/SPRY domain profile. / B30.2/SPRY domain superfamily / Domain in SPla and the RYanodine Receptor. / SPRY domain / FKBP-type peptidyl-prolyl cis-trans isomerase domain profile. / FKBP-type peptidyl-prolyl cis-trans isomerase / FKBP-type peptidyl-prolyl cis-trans isomerase domain / Peptidyl-prolyl cis-trans isomerase domain superfamily / EF-hand calcium-binding domain profile. / EF-hand domain / Ion transport domain / Ion transport protein / EF-hand domain pair / Concanavalin A-like lectin/glucanase domain superfamily
Similarity search - Domain/homology
ADENOSINE-5'-TRIPHOSPHATE / CAFFEINE / Ryanodine receptor 3 / Peptidyl-prolyl cis-trans isomerase FKBP1B
Similarity search - Component
Biological speciesHomo sapiens (human)
Neogale vison (American mink)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.22 Å
AuthorsChen, Y.S. / Van Petegem, F.
Funding support Canada, 3items
OrganizationGrant numberCountry
Canadian Institutes of Health Research (CIHR)PJT-159601 Canada
Fonds de Recherche du Quebec - Sante (FRQS)BF7-310936 Canada
Other governmentRT-2023-3133
CitationJournal: Nat Commun / Year: 2024
Title: Cryo-EM investigation of ryanodine receptor type 3.
Authors: Yu Seby Chen / Maricela Garcia-Castañeda / Maria Charalambous / Daniela Rossi / Vincenzo Sorrentino / Filip Van Petegem /
Abstract: Ryanodine Receptor isoform 3 (RyR3) is a large ion channel found in the endoplasmic reticulum membrane of many different cell types. Within the hippocampal region of the brain, it is found in ...Ryanodine Receptor isoform 3 (RyR3) is a large ion channel found in the endoplasmic reticulum membrane of many different cell types. Within the hippocampal region of the brain, it is found in dendritic spines and regulates synaptic plasticity. It controls myogenic tone in arteries and is upregulated in skeletal muscle in early development. RyR3 has a unique functional profile with a very high sensitivity to activating ligands, enabling high gain in Ca-induced Ca release. Here we solve high-resolution cryo-EM structures of RyR3 in non-activating and activating conditions, revealing structural transitions that occur during channel opening. Addition of activating ligands yields only open channels, indicating an intrinsically high open probability under these conditions. RyR3 has reduced binding affinity to the auxiliary protein FKBP12.6 due to several sequence variations in the binding interface. We map disease-associated sequence variants and binding sites for known pharmacological agents. The N-terminal region contains ligand binding sites for a putative chloride anion and ATP, both of which are targeted by sequence variants linked to epileptic encephalopathy.
History
DepositionMay 29, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 16, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 20, 2024Group: Data collection / Category: em_admin / Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Peptidyl-prolyl cis-trans isomerase FKBP1B
B: Ryanodine receptor 3
C: Peptidyl-prolyl cis-trans isomerase FKBP1B
D: Ryanodine receptor 3
E: Peptidyl-prolyl cis-trans isomerase FKBP1B
F: Ryanodine receptor 3
G: Peptidyl-prolyl cis-trans isomerase FKBP1B
H: Ryanodine receptor 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)2,258,02632
Polymers2,252,6288
Non-polymers5,39824
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Protein , 2 types, 8 molecules ACEGBDFH

#1: Protein
Peptidyl-prolyl cis-trans isomerase FKBP1B / PPIase FKBP1B / 12.6 kDa FK506-binding protein / FKBP-12.6 / FK506-binding protein 1B / FKBP-1B / ...PPIase FKBP1B / 12.6 kDa FK506-binding protein / FKBP-12.6 / FK506-binding protein 1B / FKBP-1B / Immunophilin FKBP12.6 / Rotamase / h-FKBP-12


Mass: 11939.562 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 BL21(DE3) (bacteria) / Variant (production host): Rosetta / References: UniProt: P68106, peptidylprolyl isomerase
#2: Protein
Ryanodine receptor 3


Mass: 551217.375 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Neogale vison (American mink) / Gene: RYR3 / Cell line (production host): HEK293T / Production host: Homo sapiens (human) / References: UniProt: A0A8C7B9Y8

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Non-polymers , 5 types, 24 molecules

#3: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#4: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Ca / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical
ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE


Mass: 507.181 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / Feature type: SUBJECT OF INVESTIGATION / Comment: ATP, energy-carrying molecule*YM
#6: Chemical
ChemComp-CFF / CAFFEINE / 3,7-DIHYDRO-1,3,7-TRIMETHYL-1H-PURINE-2,6-DIONE


Mass: 194.191 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C8H10N4O2 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication*YM
#7: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Cl / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY
Has protein modificationY

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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: mink RyR3 + FKBP12.6 / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightValue: 2.25 MDa / Experimental value: YES
Source (natural)Organism: Neogale vison (American mink)
Source (recombinant)Organism: Homo sapiens (human) / Cell: HEK293T
Buffer solutionpH: 7.5
Details: 20 mM HEPES pH 7.5, 250 mM NaCl, 2 mM DTT, 0.02% GDN, 0.03 mM free Ca2+ buffered with 2 mM EGTA, 5 mM ATP, 5 mM caffeine, 1:1000 diluted protease inhibitor cocktail
SpecimenConc.: 5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277.15 K
Details: blotted for 3 s (blot force of 7 to 10) using ashless blotting paper (Whatman)

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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: 2000 nm / Nominal defocus min: 500 nm / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 50 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) / Num. of grids imaged: 3 / Num. of real images: 10099
EM imaging opticsEnergyfilter name: TFS Selectris

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4.3.0particle selection
2crYOLO1.9.7particle selection
3EPUimage acquisition
5cryoSPARC4.3.0CTF correction
8UCSF ChimeraX1.7model fitting
9Coot0.9.8.92model fitting
11cryoSPARC4.3.0initial Euler assignment
12cryoSPARC4.3.0final Euler assignment
14cryoSPARC4.4.13D reconstruction
15PHENIX1.20.1model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 162679
SymmetryPoint symmetry: C4 (4 fold cyclic)
3D reconstructionResolution: 3.22 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 84690 / Algorithm: FOURIER SPACE / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: REAL / Target criteria: cross-correlation coefficient
Atomic model buildingPDB-ID: 9C1E

9c1e


Accession code: 9C1E / Details: mink RyR3 in closed conformation / Source name: PDB / Type: experimental model

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