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- EMDB-70575: Cryo-EM Structure of Ryanodine Receptor 1: DMSO Control N-termina... -

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Basic information

Entry
Database: EMDB / ID: EMD-70575
TitleCryo-EM Structure of Ryanodine Receptor 1: DMSO Control N-terminal Domain Locally Refined Map
Map dataNTD Local Refinement
Sample
  • Complex: Tetrameric complex of RyR1 with FKBP12.6
KeywordsIon channel / Calcium Channel / TRANSPORT PROTEIN
Biological speciesOryctolagus cuniculus (rabbit)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.86 Å
AuthorsMolinarolo SM / Van Petegem F
Funding support Canada, 1 items
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, 2025-
Header (metadata) releaseJan 21, 2026-
Map releaseJan 21, 2026-
UpdateJan 21, 2026-
Current statusJan 21, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_70575.png

Downloads & links

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Map

FileDownload / File: emd_70575.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationNTD Local Refinement
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.96 Å/pix.
x 512 pix.
= 491.52 Å		0.96 Å/pix.
x 512 pix.
= 491.52 Å		0.96 Å/pix.
x 512 pix.
= 491.52 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.96 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.061
Minimum - Maximum-0.069682494 - 0.20685495
Average (Standard dev.)0.0004510859 (±0.005518186)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 491.52 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: NTD Local Refinement - Half A

Fileemd_70575_half_map_1.map
AnnotationNTD Local Refinement - Half A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: NTD Local Refinement - Half B

Fileemd_70575_half_map_2.map
AnnotationNTD Local Refinement - Half B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Tetrameric complex of RyR1 with FKBP12.6

EntireName: Tetrameric complex of RyR1 with FKBP12.6
Components
  • Complex: Tetrameric complex of RyR1 with FKBP12.6

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Supramolecule #1: Tetrameric complex of RyR1 with FKBP12.6

SupramoleculeName: Tetrameric complex of RyR1 with FKBP12.6 / type: complex / ID: 1 / Parent: 0
Source (natural)Organism: Oryctolagus cuniculus (rabbit)
Molecular weightTheoretical: 2.39 MDa

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration10 mg/mL
BufferpH: 7.5
Component:
ConcentrationName
2.0 %DMSO
2.0 mMCaffeine
36.0 uMFree Ca2+
2.0 mMEGTA
25.0 mMTris
250.0 mMSodium Chloride
0.5 mMTCEP
0.5 mMBenzamidine
0.375 %CHAPS
0.001 %DOPC
GridModel: Quantifoil R2/2 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 25 sec. / Pretreatment - Atmosphere: AIR / Pretreatment - Pressure: 3.9e-05 kPa
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Name: TFS Selectris
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Number grids imaged: 1 / Number real images: 4140 / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: DARK FIELD / Cs: 2.7 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.5 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: cryoSPARC (ver. 4.4.1) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7tzc

Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.86 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.4.1) / Number images used: 126217
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.4.1)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.4.1)
Final 3D classificationSoftware - Name: cryoSPARC (ver. 4.4.1)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

7tzc


Chain - Chain ID: A / Chain - Residue range: 1-5037 / Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: RIGID BODY FIT

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