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- PDB-9e17: Structure of RyR1 in the primed state in the presence of caffeine... -

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Basic information

Entry
Database: PDB / ID: 9.0E+17
TitleStructure of RyR1 in the primed state in the presence of caffeine (reprocessed/reanalyzed from EMPIAR-10997, 7TZC, EMD-26205)
Components
  • Calmodulin-1
  • 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-sensitive calcium-release channel activity / ryanodine receptor complex / release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / CaM pathway / Cam-PDE 1 activation / ossification involved in bone maturation / Sodium/Calcium exchangers ...cytoplasmic side of membrane / ATP-gated ion channel activity / terminal cisterna / ryanodine-sensitive calcium-release channel activity / ryanodine receptor complex / release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / CaM pathway / Cam-PDE 1 activation / ossification involved in bone maturation / Sodium/Calcium exchangers / Calmodulin induced events / cellular response to caffeine / Reduction of cytosolic Ca++ levels / Activation of Ca-permeable Kainate Receptor / CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde / Loss of phosphorylation of MECP2 at T308 / CREB1 phosphorylation through the activation of Adenylate Cyclase / skin development / negative regulation of high voltage-gated calcium channel activity / PKA activation / CaMK IV-mediated phosphorylation of CREB / Glycogen breakdown (glycogenolysis) / CLEC7A (Dectin-1) induces NFAT activation / Activation of RAC1 downstream of NMDARs / negative regulation of ryanodine-sensitive calcium-release channel activity / organelle localization by membrane tethering / mitochondrion-endoplasmic reticulum membrane tethering / autophagosome membrane docking / negative regulation of calcium ion export across plasma membrane / regulation of ryanodine-sensitive calcium-release channel activity / regulation of cardiac muscle cell action potential / organelle membrane / presynaptic endocytosis / Synthesis of IP3 and IP4 in the cytosol / intracellularly gated calcium channel activity / Phase 0 - rapid depolarisation / smooth endoplasmic reticulum / Negative regulation of NMDA receptor-mediated neuronal transmission / outflow tract morphogenesis / Unblocking of NMDA receptors, glutamate binding and activation / RHO GTPases activate PAKs / calcineurin-mediated signaling / regulation of cell communication by electrical coupling involved in cardiac conduction / Ion transport by P-type ATPases / Uptake and function of anthrax toxins / intracellular membrane-bounded organelle / protein phosphatase activator activity / Long-term potentiation / Calcineurin activates NFAT / Regulation of MECP2 expression and activity / DARPP-32 events / Smooth Muscle Contraction / detection of calcium ion / toxic substance binding / regulation of cardiac muscle contraction / voltage-gated calcium channel activity / catalytic complex / RHO GTPases activate IQGAPs / calcium channel inhibitor activity / presynaptic cytosol / striated muscle contraction / Activation of AMPK downstream of NMDARs / cellular response to interferon-beta / skeletal muscle fiber development / Protein methylation / Ion homeostasis / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / eNOS activation / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / titin binding / regulation of calcium-mediated signaling / release of sequestered calcium ion into cytosol / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / voltage-gated potassium channel complex / FCERI mediated Ca+2 mobilization / sarcoplasmic reticulum membrane / calcium channel complex / substantia nigra development / FCGR3A-mediated IL10 synthesis / regulation of heart rate / cellular response to calcium ion / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / Ras activation upon Ca2+ influx through NMDA receptor / muscle contraction / calyx of Held / adenylate cyclase activator activity / VEGFR2 mediated cell proliferation / VEGFR2 mediated vascular permeability / sarcomere / regulation of cytokinesis / protein serine/threonine kinase activator activity / sarcoplasmic reticulum / spindle microtubule / peptidylprolyl isomerase / positive regulation of receptor signaling pathway via JAK-STAT / peptidyl-prolyl cis-trans isomerase activity / Translocation of SLC2A4 (GLUT4) to the plasma membrane / calcium channel regulator activity / Transcriptional activation of mitochondrial biogenesis / RAF activation
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. / FKBP-type peptidyl-prolyl cis-trans isomerase / FKBP-type peptidyl-prolyl cis-trans isomerase domain / FKBP-type peptidyl-prolyl cis-trans isomerase domain profile. / B30.2/SPRY domain superfamily / Domain in SPla and the RYanodine Receptor. / SPRY domain / Peptidyl-prolyl cis-trans isomerase domain superfamily / : / EF-hand domain pair / EF-hand, calcium binding motif / EF-Hand 1, calcium-binding site / EF-hand calcium-binding domain. / EF-hand calcium-binding domain profile. / EF-hand domain / Ion transport domain / Ion transport protein / EF-hand domain pair / Concanavalin A-like lectin/glucanase domain superfamily
Similarity search - Domain/homology
ADENOSINE-5'-TRIPHOSPHATE / CAFFEINE / Chem-KVR / Chem-L9R / Calmodulin-1 / Ryanodine receptor 1 / Peptidyl-prolyl cis-trans isomerase FKBP1A
Similarity search - Component
Biological speciesHomo sapiens (human)
Oryctolagus cuniculus (rabbit)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.45 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 1.1Jun 25, 2025Group: Database references / Category: citation / citation_author
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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
K: Calmodulin-1
F: Peptidyl-prolyl cis-trans isomerase FKBP1A
D: Calmodulin-1
E: Calmodulin-1
C: Calmodulin-1
A: Ryanodine receptor 1
H: Peptidyl-prolyl cis-trans isomerase FKBP1A
J: Peptidyl-prolyl cis-trans isomerase FKBP1A
O: Peptidyl-prolyl cis-trans isomerase FKBP1A
B: Ryanodine receptor 1
G: Ryanodine receptor 1
I: Ryanodine receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)2,392,98860
Polymers2,379,46812
Non-polymers13,52048
Water724
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 , 3 types, 12 molecules KDECFHJOABGI

#1: Protein
Calmodulin-1


Mass: 16990.691 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CALM1, CALM, CAM, CAM1 / Production host: Escherichia coli (E. coli) / References: UniProt: P0DP23
#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
#3: 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

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Non-polymers , 7 types, 52 molecules

#4: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 20 / Source method: obtained synthetically / Formula: Ca
#5: Chemical
ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE


Mass: 507.181 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / Comment: ATP, energy-carrying molecule*YM
#6: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#7: Chemical
ChemComp-CFF / CAFFEINE / 3,7-DIHYDRO-1,3,7-TRIMETHYL-1H-PURINE-2,6-DIONE


Mass: 194.191 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C8H10N4O2 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication*YM
#8: Chemical
ChemComp-KVR / 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl]benzoic acid


Mass: 329.413 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C18H19NO3S
#9: Chemical
ChemComp-L9R / (2S)-3-(octadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / 1-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine


Mass: 788.129 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C44H86NO8P / Comment: SOPC, phospholipid*YM
#10: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: H2O

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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 in complex with calstabin-1 and calmodulin / Type: COMPLEX / Entity ID: #1-#3 / Source: NATURAL
Source (natural)Organism: Oryctolagus cuniculus (rabbit)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen 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: 2000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 57.65 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.45 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 333010 / Symmetry type: POINT
Atomic model buildingPDB-ID: 7TZC

7tzc


Accession code: 7TZC / Source name: PDB / Type: experimental model

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