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- EMDB-74359: Structure of RY12 domain of rabbit RyR1 in the presence of ATP, M... -

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Basic information

Entry
Database: EMDB / ID: EMD-74359
TitleStructure of RY12 domain of rabbit RyR1 in the presence of ATP, Mg2+, and Ca2+ (open RY12 conformation)
Map data
Sample
  • Complex: RyR1 complexed with FKBP12.6 and calmodulin
    • Protein or peptide: Ryanodine receptor 1
Keywordssarcoplasmic reticulum / intracellular calcium channel / excitation-contraction coupling / complex / MEMBRANE PROTEIN
Function / homology
Function and homology information


ATP-gated ion channel activity / terminal cisterna / ryanodine-sensitive calcium-release channel activity / ossification involved in bone maturation / release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / skin development / cellular response to caffeine / ryanodine receptor complex / organelle membrane / outflow tract morphogenesis ...ATP-gated ion channel activity / terminal cisterna / ryanodine-sensitive calcium-release channel activity / ossification involved in bone maturation / release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / skin development / cellular response to caffeine / ryanodine receptor complex / organelle membrane / outflow tract morphogenesis / smooth endoplasmic reticulum / intracellularly gated calcium channel activity / toxic substance binding / skeletal muscle fiber development / voltage-gated calcium channel activity / release of sequestered calcium ion into cytosol / cellular response to calcium ion / muscle contraction / sarcoplasmic reticulum membrane / sarcoplasmic reticulum / striated muscle contraction / sarcolemma / intracellular calcium ion homeostasis / calcium channel activity / Z disc / calcium ion transmembrane transport / disordered domain specific binding / calmodulin binding / protein homotetramerization / transmembrane transporter binding / calcium ion binding / ATP binding / membrane / identical protein binding
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 / Ion transport domain / Ion transport protein / EF-hand domain pair / Concanavalin A-like lectin/glucanase domain superfamily
Similarity search - Domain/homology
Ryanodine receptor 1
Similarity search - Component
Biological speciesOryctolagus cuniculus (rabbit)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.64 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 5, 2025-
Header (metadata) releaseSep 16, 2026-
Map releaseSep 16, 2026-
UpdateOct 21, 2026-
Current statusOct 21, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_74359.png

Downloads & links

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Map

FileDownload / File: emd_74359.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

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AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 256 pix.
= 212.48 Å		0.83 Å/pix.
x 256 pix.
= 212.48 Å		0.83 Å/pix.
x 256 pix.
= 212.48 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.83 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.7
Minimum - Maximum-6.6844907 - 9.119907
Average (Standard dev.)0.008045303 (±0.07927099)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 212.48 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_74359_msk_1.map
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Half map: #2

Fileemd_74359_half_map_1.map
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Half map: #1

Fileemd_74359_half_map_2.map
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Sample components

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Entire : RyR1 complexed with FKBP12.6 and calmodulin

EntireName: RyR1 complexed with FKBP12.6 and calmodulin
Components
  • Complex: RyR1 complexed with FKBP12.6 and calmodulin
    • Protein or peptide: Ryanodine receptor 1

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Supramolecule #1: RyR1 complexed with FKBP12.6 and calmodulin

SupramoleculeName: RyR1 complexed with FKBP12.6 and calmodulin / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Oryctolagus cuniculus (rabbit)

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Macromolecule #1: Ryanodine receptor 1

MacromoleculeName: Ryanodine receptor 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Oryctolagus cuniculus (rabbit)
Molecular weightTheoretical: 23.807158 KDa
SequenceString: DFVPCPVDTV QIVLPPHLER IREKLAENIH ELWALTRIEQ GWTYGPVRDD NKRLHPCLVN FHSLPEPERN YNLQMSGETL KTLLALGCH VGMADEKAED NLKKTKLPKT YMMSNGYKPA PLDLSHVRLT PAQTTLVDRL AENGHNVWAR DRVAQGWSYS A VQDIPARR ...String:
DFVPCPVDTV QIVLPPHLER IREKLAENIH ELWALTRIEQ GWTYGPVRDD NKRLHPCLVN FHSLPEPERN YNLQMSGETL KTLLALGCH VGMADEKAED NLKKTKLPKT YMMSNGYKPA PLDLSHVRLT PAQTTLVDRL AENGHNVWAR DRVAQGWSYS A VQDIPARR NPRLVPYRLL DEATKRSNRD SLCQAVRTLL GYGYNIEPPD

UniProtKB: Ryanodine receptor 1

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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 K3 BIOQUANTUM (6k x 4k) / Detector mode: COUNTING / Average electron dose: 58.0 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: 2.64 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 328980
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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