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- PDB-9e1e: Structure of RyR1 in the primed state in the presence of uracil -

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Basic information

Entry
Database: PDB / ID: 9e1e
TitleStructure of RyR1 in the primed state in the presence of uracil
Components
  • Peptidyl-prolyl cis-trans isomerase FKBP1A
  • Ryanodine receptor 1
KeywordsTRANSPORT PROTEIN / calcium channel / sarcoplasmic reticulum
Function / homology
Function and homology information


cytoplasmic side of membrane / ATP-gated ion channel activity / terminal cisterna / ryanodine receptor complex / ryanodine-sensitive calcium-release channel activity / release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / ossification involved in bone maturation / cellular response to caffeine / skin development / organelle membrane ...cytoplasmic side of membrane / ATP-gated ion channel activity / terminal cisterna / ryanodine receptor complex / ryanodine-sensitive calcium-release channel activity / release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / ossification involved in bone maturation / cellular response to caffeine / skin development / organelle membrane / intracellularly gated calcium channel activity / smooth endoplasmic reticulum / outflow tract morphogenesis / regulation of ryanodine-sensitive calcium-release channel activity / toxic substance binding / striated muscle contraction / voltage-gated calcium channel activity / skeletal muscle fiber development / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / release of sequestered calcium ion into cytosol / sarcoplasmic reticulum membrane / muscle contraction / cellular response to calcium ion / sarcoplasmic reticulum / peptidylprolyl isomerase / peptidyl-prolyl cis-trans isomerase activity / sarcolemma / calcium ion transmembrane transport / calcium channel activity / Z disc / intracellular calcium ion homeostasis / disordered domain specific binding / protein homotetramerization / transmembrane transporter binding / calmodulin binding / intracellular membrane-bounded organelle / calcium ion binding / ATP binding / identical protein binding / membrane / cytosol
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 / FKBP-type peptidyl-prolyl cis-trans isomerase / FKBP-type peptidyl-prolyl cis-trans isomerase domain / FKBP-type peptidyl-prolyl cis-trans isomerase domain profile. / 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 / URACIL / Ryanodine receptor 1 / Peptidyl-prolyl cis-trans isomerase FKBP1A
Similarity search - Component
Biological speciesOryctolagus cuniculus (rabbit)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.92 Å
AuthorsMiotto, M.C. / Marks, A.R.
Funding support1items
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, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 30, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 13, 2024Group: Data collection / Category: em_admin / Item: _em_admin.last_update
Revision 1.2Jun 25, 2025Group: 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 / _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
E: Peptidyl-prolyl cis-trans isomerase FKBP1A
H: Peptidyl-prolyl cis-trans isomerase FKBP1A
G: Peptidyl-prolyl cis-trans isomerase FKBP1A
F: Peptidyl-prolyl cis-trans isomerase FKBP1A
B: Ryanodine receptor 1
D: Ryanodine receptor 1
C: Ryanodine receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)2,314,40424
Polymers2,311,5058
Non-polymers2,89916
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 2 types, 8 molecules ABDCEHGF

#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: 565908.625 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Source: (natural) Oryctolagus cuniculus (rabbit) / References: UniProt: P11716
#2: Protein
Peptidyl-prolyl cis-trans isomerase FKBP1A / PPIase FKBP1A / 12 kDa FK506-binding protein / 12 kDa FKBP / FKBP-12 / Calstabin-1 / FK506-binding ...PPIase FKBP1A / 12 kDa FK506-binding protein / 12 kDa FKBP / FKBP-12 / Calstabin-1 / FK506-binding protein 1A / FKBP-1A / Immunophilin FKBP12 / Rotamase


Mass: 11967.705 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Source: (natural) Oryctolagus cuniculus (rabbit) / References: UniProt: P62943, peptidylprolyl isomerase

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Non-polymers , 4 types, 16 molecules

#3: Chemical
ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE


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


Mass: 40.078 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Ca
#5: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#6: Chemical
ChemComp-URA / URACIL


Mass: 112.087 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C4H4N2O2 / 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

Component
IDNameTypeEntity IDParent-IDSourceDetails
1Complex of RyR1 and Calstabin-1COMPLEX#1-#20NATURAL
2Ryanodine Receptor 1COMPLEX#11NATURAL
3Calstabin-1COMPLEX#21NATURALPeptidyl- cis-trans isomerase FKBP1A
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Oryctolagus cuniculus (rabbit)9986
33Oryctolagus cuniculus (rabbit)9986
Buffer solutionpH: 7.4
Details: 2 mM uracil was added to the final sample from a 100 mM stock solution in 100% DMSO.
Buffer component
IDConc.NameFormulaBuffer-ID
110 mMHEPESHEPES1
2500 mMsodium chlorideNaCl1
30.2 %CHAPSCHAPS1
41 mMEGTAEGTA1
50.5 mMtris(2-carboxyethyl)phosphineTCEP1
60.01 %DOPCDOPC1
710 mMATPATP1
81.6 mMcalcium chlorideCaCl21
SpecimenConc.: 10 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE

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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: 1500 nm / Nominal defocus min: 500 nm / Cs: 2.7 mm / C2 aperture diameter: 100 µm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Temperature (max): 100 K / Temperature (min): 80 K
Image recordingElectron dose: 58 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV
Image scansSampling size: 5 µm / Width: 5760 / Height: 4092

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Processing

EM software
IDNameVersionCategoryDetails
1cryoSPARCparticle selection
2Leginon3.5image acquisitionMSI-T2
4cryoSPARCCTF correction
7Cootmodel fitting
9PHENIXmodel refinement
10cryoSPARCinitial Euler assignment
12cryoSPARCclassification
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.92 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 33584 / Symmetry type: POINT
Atomic model buildingPDB-ID: 7TZC

7tzc


Accession code: 7TZC / Source name: PDB / Type: experimental model
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 100.44 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0036147400
ELECTRON MICROSCOPYf_angle_d0.591199700
ELECTRON MICROSCOPYf_chiral_restr0.040921916
ELECTRON MICROSCOPYf_plane_restr0.004525948
ELECTRON MICROSCOPYf_dihedral_angle_d5.148119903

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