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- PDB-9ol6: Rabbit Ryanodine Receptor 1: DMSO Control Closed Conformation -

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Basic information

Entry
Database: PDB / ID: 9ol6
TitleRabbit Ryanodine Receptor 1: DMSO Control Closed Conformation
Components
  • Peptidyl-prolyl cis-trans isomerase FKBP1B
  • Ryanodine receptor 1
KeywordsTRANSPORT PROTEIN / Ion channel / Calcium Channel
Function / homology
Function and homology information


ATP-gated ion channel activity / positive regulation of sequestering of calcium ion / negative regulation of calcium-mediated signaling / negative regulation of insulin secretion involved in cellular response to glucose stimulus / neuronal action potential propagation / negative regulation of release of sequestered calcium ion into cytosol / insulin secretion involved in cellular response to glucose stimulus / terminal cisterna / ryanodine-sensitive calcium-release channel activity / ryanodine receptor complex ...ATP-gated ion channel activity / positive regulation of sequestering of calcium ion / negative regulation of calcium-mediated signaling / negative regulation of insulin secretion involved in cellular response to glucose stimulus / neuronal action potential propagation / negative regulation of release of sequestered calcium ion into cytosol / insulin secretion involved in cellular response to glucose stimulus / terminal cisterna / ryanodine-sensitive calcium-release channel activity / ryanodine receptor complex / release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / response to redox state / ossification involved in bone maturation / 'de novo' protein folding / negative regulation of heart rate / cellular response to caffeine / skin development / FK506 binding / organelle membrane / intracellularly gated calcium channel activity / smooth endoplasmic reticulum / outflow tract morphogenesis / smooth muscle contraction / toxic substance binding / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / T cell proliferation / striated muscle contraction / voltage-gated calcium channel activity / calcium channel inhibitor activity / skeletal muscle fiber development / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / Ion homeostasis / release of sequestered calcium ion into cytosol / calcium channel complex / sarcoplasmic reticulum membrane / cellular response to calcium ion / muscle contraction / protein maturation / sarcoplasmic reticulum / calcium channel regulator activity / peptidylprolyl isomerase / peptidyl-prolyl cis-trans isomerase activity / calcium-mediated signaling / sarcolemma / calcium ion transmembrane transport / Stimuli-sensing channels / calcium channel activity / Z disc / intracellular calcium ion homeostasis / disordered domain specific binding / positive regulation of cytosolic calcium ion concentration / protein refolding / protein homotetramerization / transmembrane transporter binding / calmodulin binding / signaling receptor binding / calcium ion binding / ATP binding / identical protein 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 / FKBP-type peptidyl-prolyl cis-trans isomerase domain / FKBP-type peptidyl-prolyl cis-trans isomerase domain profile. / Peptidyl-prolyl cis-trans isomerase domain superfamily / Ion transport domain / Ion transport protein / EF-hand domain pair / Concanavalin A-like lectin/glucanase domain superfamily
Similarity search - Domain/homology
Ryanodine receptor 1 / Peptidyl-prolyl cis-trans isomerase FKBP1B
Similarity search - Component
Biological speciesHomo sapiens (human)
Oryctolagus cuniculus (rabbit)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.11 Å
AuthorsMolinarolo, S.M. / Van Petegem, F.
Funding support Canada, 1items
OrganizationGrant numberCountry
Canadian Institutes of Health Research (CIHR) Canada
CitationJournal: Nat Commun / Year: 2025
Title: Cryo-electron microscopy reveals sequential binding and activation of Ryanodine Receptors by statin triplets.
Authors: Steven Molinarolo / Carmen R Valdivia / Héctor H Valdivia / Filip Van Petegem /
Abstract: Statins are the most prescribed class of drugs and inhibit a key enzyme in the cholesterol biosynthesis pathway. Many patients have reported mild to severe muscle related symptoms and a subset are at ...Statins are the most prescribed class of drugs and inhibit a key enzyme in the cholesterol biosynthesis pathway. Many patients have reported mild to severe muscle related symptoms and a subset are at risk for rhabdomyolysis. Sequence variants in RyR1, the skeletal muscle Ryanodine Receptor, correlate with intolerance to statins, but whether RyR1 can bind statins directly has remained unclear. Here we report cryo-EM structures of RyR1 in the absence and presence of atorvastatin, firmly establishing RyR1 as an unintended off-target. Our results show an unusual binding mode whereby three atorvastatin molecules bind together in a cleft formed by the pseudo-voltage sensing domain, making extensive interactions with each other and with RyR1. Atorvastatin activates RyR1 in a sequential way, whereby one statin per subunit can bind to the transmembrane region of a closed RyR1, with small structural perturbations that prime the channel for opening. Binding of two additional statins per subunit is associated with a widening of the pseudo-voltage sensing domain that triggers opening of the pore. Comparison with atorvastatin binding to HMG-CoA reductase, its intended target, offers clues on how to modify the statin to reduce RyR1 binding, while leaving binding to HMG-CoA reductase unperturbed.
History
DepositionMay 12, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 3, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Ryanodine receptor 1
B: Peptidyl-prolyl cis-trans isomerase FKBP1B
G: Ryanodine receptor 1
H: Peptidyl-prolyl cis-trans isomerase FKBP1B
M: Ryanodine receptor 1
N: Peptidyl-prolyl cis-trans isomerase FKBP1B
S: Ryanodine receptor 1
T: Peptidyl-prolyl cis-trans isomerase FKBP1B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)2,312,33916
Polymers2,311,9188
Non-polymers4228
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Ryanodine receptor 1 / RYR-1 / RyR1 / Skeletal muscle calcium release channel / Skeletal muscle ryanodine receptor / ...RYR-1 / RyR1 / Skeletal muscle calcium release channel / Skeletal muscle ryanodine receptor / Skeletal muscle-type ryanodine receptor / Type 1 ryanodine receptor


Mass: 565908.625 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Source: (natural) Oryctolagus cuniculus (rabbit) / References: UniProt: P11716
#2: 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: 12070.759 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-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Ca
#4: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
Has ligand of interestN
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: Tetrameric complex of RyR1 with FKBP12.6 / Type: COMPLEX / Entity ID: #1-#2 / Source: MULTIPLE SOURCES
Molecular weightValue: 2.39 MDa / Experimental value: NO
Source (natural)Organism: Oryctolagus cuniculus (rabbit)
Buffer solutionpH: 7.5
Buffer component
IDConc.NameBuffer-ID
12 %DMSO1
22 mMCaffeine1
336 uMFree Ca2+1
42 mMEGTA1
525 mMTris1
6250 mMSodium Chloride1
70.5 mMTCEP1
80.5 mMBenzamidine1
90.375 %CHAPS1
100.001 %DOPC1
SpecimenConc.: 10 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R2/2
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277.15 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 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: 1 / Num. of real images: 4140
EM imaging opticsEnergyfilter name: TFS Selectris

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Processing

EM software
IDNameVersionCategoryDetails
1Topaz0.2.3particle selection
4cryoSPARC4.4.1CTF correction
7PHENIX1.21.1model fittingRigid body fitting of map pieces
9PHENIX1.21.1model refinementReal Space Refinement
10ISOLDE1.7.1model refinementModel Geometry Optimization
11cryoSPARC4.4.1initial Euler assignment
12cryoSPARC4.4.1final Euler assignment
13cryoSPARC4.4.1classification
14cryoSPARC4.4.13D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.11 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 126217 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: REAL
Atomic model buildingPDB-ID: 7TZC

7tzc


Pdb chain-ID: A / Accession code: 7TZC / Chain residue range: 1-5037 / Pdb chain residue range: 1-5037 / Source name: PDB / Type: experimental model

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