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- EMDB-74294: Focused map of rabbit RyR1 complexed with FKBP12.6, calmodulin, A... -

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Basic information

Entry
Database: EMDB / ID: EMD-74294
TitleFocused map of rabbit RyR1 complexed with FKBP12.6, calmodulin, ATP, and 4-chloro-m-cresol (JSol mask)
Map data
Sample
  • Complex: RyR1 complexed with FKBP12.6, calmodulin, ATP, and 4-chloro-m-cresol
Keywordssarcoplasmic reticulum / intracellular calcium channel / excitation-contraction coupling / complex / MEMBRANE PROTEIN
Biological speciesOryctolagus cuniculus (rabbit)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.48 Å
AuthorsKim K / Clarke OB
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH/NIAMS)R01AR077720 United States
CitationJournal: Nat Commun / Year: 2026
Title: Structural identification of the RY12 domain of RyR1 as an ADP sensor and the target of the malignant hyperthermia therapeutic dantrolene.
Authors: Kookjoo Kim / Huan Li / Qi Yuan / Zephan Melville / Ran Zalk / Amédée des Georges / Joachim Frank / Wayne A Hendrickson / Andrew R Marks / Oliver B Clarke /
Abstract: Malignant hyperthermia (MH) is a pharmacogenetic condition triggered by volatile anesthetics, which activate MH susceptible mutants of ryanodine receptor 1 (RyR1). The precise binding sites and ...Malignant hyperthermia (MH) is a pharmacogenetic condition triggered by volatile anesthetics, which activate MH susceptible mutants of ryanodine receptor 1 (RyR1). The precise binding sites and mechanisms of the therapeutic dantrolene and MH triggers have remained unclear. Here, we present structures of RyR1 bound to dantrolene and the MH trigger 4-chloro-m-cresol (4CmC), revealing the dantrolene and 4CmC binding sites in atomic detail. Dantrolene binds stacked with ATP or ADP in the RY12 domain at the corner of the receptor, inducing a conformational change. Functional analyses confirm ATP or ADP is required for dantrolene inhibition, and a single point mutation disrupting this peripheral ATP site abolishes this ATP/ADP-dependent inhibition. Strikingly, in the absence of dantrolene, this site selectively binds two ADP molecules even in the presence of excess ATP, indicating a role in ATP/ADP ratio sensing. Additionally, we identified four 4CmC binding sites, revealing one primary binding site in an amphipathic cavity in the core solenoid, and three auxiliary binding sites in the EF-hand, transmembrane, and RY12 domains. These findings offer insights into the binding modes and mechanisms of MH-linked molecules, and reveal the RY12 domain's regulatory role as a promiscuous sensor for adenine nucleotides and small ligands.
History
DepositionDec 4, 2025-
Header (metadata) releaseSep 16, 2026-
Map releaseSep 16, 2026-
UpdateOct 28, 2026-
Current statusOct 28, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_74294.png

Downloads & links

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Map

FileDownload / File: emd_74294.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.06 Å/pix.
x 512 pix.
= 542.72 Å		1.06 Å/pix.
x 512 pix.
= 542.72 Å		1.06 Å/pix.
x 512 pix.
= 542.72 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.06 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 1.5
Minimum - Maximum-5.300468 - 8.4489565
Average (Standard dev.)0.0020382316 (±0.12560141)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 542.72 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_74294_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_74294_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_74294_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 : RyR1 complexed with FKBP12.6, calmodulin, ATP, and 4-chloro-m-cresol

EntireName: RyR1 complexed with FKBP12.6, calmodulin, ATP, and 4-chloro-m-cresol
Components
  • Complex: RyR1 complexed with FKBP12.6, calmodulin, ATP, and 4-chloro-m-cresol

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Supramolecule #1: RyR1 complexed with FKBP12.6, calmodulin, ATP, and 4-chloro-m-cresol

SupramoleculeName: RyR1 complexed with FKBP12.6, calmodulin, ATP, and 4-chloro-m-cresol
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
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

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average electron dose: 71.2 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.48 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 1037448
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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