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- PDB-9cgq: Rabbit RyR1 disease mutant Y523S in complex with FKBP12.6, nanodi... -

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Basic information

Entry
Database: PDB / ID: 9cgq
TitleRabbit RyR1 disease mutant Y523S in complex with FKBP12.6, nanodisc and inhibitor dantrolene in the presence of activating calcium
Components
  • Peptidyl-prolyl cis-trans isomerase FKBP1B
  • Ryanodine receptor 1
KeywordsMEMBRANE PROTEIN / Ryanodine receptor / Calcium channel / Mutation / Y523S / RyR1 / dantrolene
Function / homology
Function and homology information


negative regulation of calcium-mediated signaling / ATP-gated ion channel activity / negative regulation of release of sequestered calcium ion into cytosol / response to redox state / ryanodine-sensitive calcium-release channel activity / terminal cisterna / negative regulation of heart rate / release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / ossification involved in bone maturation / cellular response to caffeine ...negative regulation of calcium-mediated signaling / ATP-gated ion channel activity / negative regulation of release of sequestered calcium ion into cytosol / response to redox state / ryanodine-sensitive calcium-release channel activity / terminal cisterna / negative regulation of heart rate / release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / ossification involved in bone maturation / cellular response to caffeine / skin development / ryanodine receptor complex / FK506 binding / organelle membrane / 'de novo' protein folding / outflow tract morphogenesis / smooth endoplasmic reticulum / intracellularly gated calcium channel activity / regulation of ryanodine-sensitive calcium-release channel activity / toxic substance binding / calcium channel inhibitor activity / skeletal muscle fiber development / release of sequestered calcium ion into cytosol / voltage-gated calcium channel activity / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / Ion homeostasis / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / calcium channel complex / cellular response to calcium ion / muscle contraction / sarcoplasmic reticulum membrane / calcium-mediated signaling / calcium channel regulator activity / peptidylprolyl isomerase / sarcoplasmic reticulum / peptidyl-prolyl cis-trans isomerase activity / striated muscle contraction / protein refolding / sarcolemma / intracellular calcium ion homeostasis / protein maturation / calcium channel activity / Z disc / Stimuli-sensing channels / calcium ion transmembrane transport / disordered domain specific binding / protein folding / calmodulin binding / protein homotetramerization / transmembrane transporter binding / signaling receptor binding / calcium ion binding / ATP binding / membrane / identical protein binding / 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 / FKBP-type peptidyl-prolyl cis-trans isomerase / FKBP-type peptidyl-prolyl cis-trans isomerase domain / FKBP-type peptidyl-prolyl cis-trans isomerase domain profile. / 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 / 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
ADENOSINE-5'-TRIPHOSPHATE / : / Ryanodine receptor 1 / Peptidyl-prolyl cis-trans isomerase FKBP1B
Similarity search - Component
Biological speciesOryctolagus cuniculus (rabbit)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.23 Å
AuthorsIyer, K.A. / Samso, M.
Funding support United States, 5items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH/NIAMS)R01 AR068431 United States
American Heart Association19POST34430178 United States
Other privateMDA 352845
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)U24 GM116789 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)U24 GM116790 United States
CitationJournal: Structure / Year: 2025
Title: Dantrolene inhibition of ryanodine receptor 1 carrying the severe malignant hyperthermia mutation Y522S visualized by cryo-EM.
Authors: Kavita A Iyer / Takuya Kobayashi / Takashi Murayama / Montserrat Samsó /
Abstract: Mutations in the skeletal isoform of the ryanodine receptor 1 (RyR1) pose grave risks during anesthesia or treatment with succinylcholine muscle relaxants. These can trigger a potentially lethal ...Mutations in the skeletal isoform of the ryanodine receptor 1 (RyR1) pose grave risks during anesthesia or treatment with succinylcholine muscle relaxants. These can trigger a potentially lethal malignant hyperthermia (MH) episode via intracellular calcium increase mainly from RyR1 channel leakage. Dantrolene is the only known treatment option to prevent death. The main target of dantrolene is RyR1; however, little is known about the mechanism of inhibition. Cryoelectron microscopy (cryo-EM) structures of dantrolene bound to the severe MH Y522S RyR1 mutant in the closed and open states at 2.5-3.3 Å resolution revealed that the drug binds to the channel's cytoplasmic assembly, far from the ion gate, interacting with residues W882, W996, and R1000 in the P1 domain. The finding was validated by Ca imaging and [H]ryanodine binding in wild-type (WT) and alanine mutants. Dantrolene reduced channel opening probability by restricting the central activation module, "cooling down" the primed conformation caused by the mutation.
History
DepositionJun 30, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 11, 2024Provider: repository / Type: Initial release
Revision 1.0Dec 11, 2024Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.1Sep 16, 2026Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _em_admin.last_update
Revision 1.1Sep 16, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin
Data content type: EM metadata / EM metadata ...EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Ryanodine receptor 1
B: Ryanodine receptor 1
C: Ryanodine receptor 1
D: Ryanodine receptor 1
E: Peptidyl-prolyl cis-trans isomerase FKBP1B
F: Peptidyl-prolyl cis-trans isomerase FKBP1B
G: Peptidyl-prolyl cis-trans isomerase FKBP1B
H: Peptidyl-prolyl cis-trans isomerase FKBP1B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)2,313,70724
Polymers2,309,9998
Non-polymers3,70816
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Protein , 2 types, 8 molecules ABCDEFGH

#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: 565832.562 Da / Num. of mol.: 4 / Mutation: Y523S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Oryctolagus cuniculus (rabbit) / Gene: RYR1 / Production host: Homo sapiens (human) / 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: 11667.305 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 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: P68106, peptidylprolyl isomerase

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Non-polymers , 4 types, 16 molecules

#3: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE


Mass: 507.181 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / Feature type: SUBJECT OF INVESTIGATION / Comment: ATP, energy-carrying molecule*YM
#5: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Ca / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical
ChemComp-U1C / Dantrolene / 1-[(Z)-{[5-(4-nitrophenyl)furan-2-yl]methylidene}amino]imidazolidine-2,4-dione


Mass: 314.253 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C14H10N4O5 / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY
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: RyR1 disease mutant Y523S with FKBP12.6, nanodisc and inhibitor dantrolene in the presence of activating calcium with refined P1 domain
Type: COMPLEX / Entity ID: #1-#2 / Source: MULTIPLE SOURCES
Molecular weightValue: 2.26 MDa / Experimental value: NO
Source (natural)Organism: Oryctolagus cuniculus (rabbit)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
Buffer component
IDConc.NameFormulaBuffer-ID
120 mM3-(N-Morpholino)propanesulfonic acid sodium saltMOPS1
20.7 MSodium chlorideNaCl1
32 mMDithiothreitolDTT1
42 mMAdenosine 5-triphosphateATP1
50.825 mMCalcium ChlorideCaCl21
60.5 mMEthylene glycol-bis(beta-aminoethyl ether)-N,N,N,N-tetraacetic acidEGTA1
70.05 mMDantroleneDantrolene1
SpecimenConc.: 3 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 277 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: 2600 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm
Image recordingAverage exposure time: 2.69 sec. / Electron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 2 / Num. of real images: 12212
EM imaging opticsEnergyfilter slit width: 10 eV

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Processing

EM softwareName: PHENIX / Version: 1.20_4459: / Category: model refinement
CTF correctionType: NONE
Particle selectionNum. of particles selected: 1968209
SymmetryPoint symmetry: C4 (4 fold cyclic)
3D reconstructionResolution: 3.23 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 189847 / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT
Atomic model buildingPDB-ID: 7T65

7t65


Accession code: 7T65 / Source name: PDB / Type: experimental model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.004132496
ELECTRON MICROSCOPYf_angle_d0.566180136
ELECTRON MICROSCOPYf_dihedral_angle_d4.12218220
ELECTRON MICROSCOPYf_chiral_restr0.03820604
ELECTRON MICROSCOPYf_plane_restr0.00423380

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