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- EMDB-47401: Structure of RyR1 in the primed state in the presence of enprofyl... -

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Basic information

Entry
Database: EMDB / ID: EMD-47401
TitleStructure of RyR1 in the primed state in the presence of enprofylline, focused refinement
Map dataStructure of RyR1 in the primed state in the presence of enprofylline - focused refinement
Sample
  • Complex: Complex of RyR1 and Calstabin-1
    • Complex: Ryanodine Receptor 1
    • Complex: Calstabin-1
Keywordscalcium channel / MEMBRANE PROTEIN / sarcoplasmic reticulum
Biological speciesOryctolagus cuniculus (rabbit)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.42 Å
AuthorsMiotto MC / Marks AR
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Proc Natl Acad Sci U S A / Year: 2025
Title: Targeting ryanodine receptors with allopurinol and xanthine derivatives for the treatment of cardiac and musculoskeletal weakness disorders.
Authors: Marco C Miotto / Estefania Luna-Figueroa / Carl Tchagou / Laith Bahlouli / Steven Reiken / Haikel Dridi / Yang Liu / Gunnar Weninger / Andrew R Marks /
Abstract: Ryanodine receptors (RyRs) are intracellular Ca channels essential for muscle contraction. Caffeine, a xanthine derivative, has been known for decades to increase muscle contraction and enhance ...Ryanodine receptors (RyRs) are intracellular Ca channels essential for muscle contraction. Caffeine, a xanthine derivative, has been known for decades to increase muscle contraction and enhance activation of RyRs by increasing the sensitivity to Ca. We previously showed that xanthine, the only physiologically relevant xanthine derivative, also binds to and activates RyR2. Most xanthine derivatives and analogs are safe and widely prescribed, with the most popular being the xanthine oxidoreductase inhibitor allopurinol (~15M yearly prescriptions in USA). We propose that xanthine derivatives and analogs that enhance RyRs activity could be used for lead optimization and eventually for the treatment of the diseases that exhibit decreased muscle contraction and reduced RyRs activity, such as RyR1-related diseases, sarcopenia, and heart failure. Here, we show by cryo-EM that xanthine derivatives, analogs, and other related compounds bind to the xanthine/caffeine binding site and activate RyR1, and identify 4-oxopyrimidine as the minimal motif necessary for such interaction.
History
DepositionOct 21, 2024-
Header (metadata) releaseOct 30, 2024-
Map releaseOct 30, 2024-
UpdateJun 25, 2025-
Current statusJun 25, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_47401.png

Downloads & links

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Map

FileDownload / File: emd_47401.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationStructure of RyR1 in the primed state in the presence of enprofylline - focused refinement
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.84 Å/pix.
x 512 pix.
= 427.52 Å		0.84 Å/pix.
x 512 pix.
= 427.52 Å		0.84 Å/pix.
x 512 pix.
= 427.52 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.835 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.15
Minimum - Maximum-0.35202554 - 0.83713996
Average (Standard dev.)0.0006822434 (±0.01828208)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 427.52 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_47401_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_47401_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Complex of RyR1 and Calstabin-1

EntireName: Complex of RyR1 and Calstabin-1
Components
  • Complex: Complex of RyR1 and Calstabin-1
    • Complex: Ryanodine Receptor 1
    • Complex: Calstabin-1

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Supramolecule #1: Complex of RyR1 and Calstabin-1

SupramoleculeName: Complex of RyR1 and Calstabin-1 / type: complex / ID: 1 / Parent: 0

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Supramolecule #2: Ryanodine Receptor 1

SupramoleculeName: Ryanodine Receptor 1 / type: complex / ID: 2 / Parent: 1
Source (natural)Organism: Oryctolagus cuniculus (rabbit)

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Supramolecule #3: Calstabin-1

SupramoleculeName: Calstabin-1 / type: complex / ID: 3 / Parent: 1 / Details: Peptidyl- cis-trans isomerase FKBP1A
Source (natural)Organism: Oryctolagus cuniculus (rabbit)

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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: 7.4
Component:
ConcentrationFormulaName
10.0 mMHEPESHEPES
500.0 mMNaClsodium chloride
0.2 %CHAPSCHAPS
1.0 mMEGTAEGTA
0.5 mMTCEPtris(2-carboxyethyl)phosphine
0.01 %DOPCDOPC
10.0 mMATPATP
1.6 mMCaCl2calcium chloride

Details: 2 mM enprofylline was added to the final sample from a 100 mM stock solution in 100% DMSO.
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
TemperatureMin: 80.0 K / Max: 100.0 K
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Image recordingFilm 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 beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 100.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.5 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 / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL / In silico model: CryoSPARC ab initio
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.42 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 376360
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD

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Atomic model buiding 1

Initial modelPDB ID:

7tzc


Chain - Source name: PDB / Chain - Initial model type: experimental model

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