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- PDB-7tzc: A drug and ATP binding site in type 1 ryanodine receptor -

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Basic information

Entry
Database: PDB / ID: 7tzc
TitleA drug and ATP binding site in type 1 ryanodine receptor
Components
  • Calmodulin-1
  • Peptidyl-prolyl cis-trans isomerase FKBP1A
  • Ryanodine receptor 1
KeywordsMEMBRANE PROTEIN / ryanodine receptor / calcium / ion channel / MEMBRANE PROTEIN-ISOMERASE complex
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 / 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 receptor complex / ryanodine-sensitive calcium-release channel activity / 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 / Reduction of cytosolic Ca++ levels / Activation of Ca-permeable Kainate Receptor / CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde / skin development / Loss of phosphorylation of MECP2 at T308 / CREB1 phosphorylation through the activation of Adenylate Cyclase / PKA activation / negative regulation of high voltage-gated calcium channel activity / CaMK IV-mediated phosphorylation of CREB / Glycogen breakdown (glycogenolysis) / negative regulation of calcium ion export across plasma membrane / organelle localization by membrane tethering / Activation of RAC1 downstream of NMDARs / regulation of cardiac muscle cell action potential / mitochondrion-endoplasmic reticulum membrane tethering / CLEC7A (Dectin-1) induces NFAT activation / autophagosome membrane docking / positive regulation of ryanodine-sensitive calcium-release channel activity / Negative regulation of NMDA receptor-mediated neuronal transmission / regulation of cell communication by electrical coupling involved in cardiac conduction / Unblocking of NMDA receptors, glutamate binding and activation / negative regulation of peptidyl-threonine phosphorylation / cellular response to caffeine / Synthesis of IP3 and IP4 in the cytosol / intracellularly gated calcium channel activity / outflow tract morphogenesis / Phase 0 - rapid depolarisation / protein phosphatase activator activity / RHO GTPases activate PAKs / positive regulation of cyclic-nucleotide phosphodiesterase activity / positive regulation of phosphoprotein phosphatase activity / Long-term potentiation / Ion transport by P-type ATPases / organelle membrane / Uptake and function of anthrax toxins / Calcineurin activates NFAT / Regulation of MECP2 expression and activity / catalytic complex / DARPP-32 events / detection of calcium ion / toxic substance binding / negative regulation of ryanodine-sensitive calcium-release channel activity / Smooth Muscle Contraction / voltage-gated calcium channel activity / RHO GTPases activate IQGAPs / regulation of cardiac muscle contraction / calcium channel inhibitor activity / cellular response to interferon-beta / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / Protein methylation / skeletal muscle fiber development / voltage-gated potassium channel complex / Activation of AMPK downstream of NMDARs / eNOS activation / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / regulation of calcium-mediated signaling / release of sequestered calcium ion into cytosol / positive regulation of protein dephosphorylation / titin binding / regulation of ryanodine-sensitive calcium-release channel activity / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / Ion homeostasis / positive regulation of protein autophosphorylation / sperm midpiece / sarcoplasmic reticulum membrane / calcium channel complex / substantia nigra development / cellular response to calcium ion / adenylate cyclase activator activity / Ras activation upon Ca2+ influx through NMDA receptor / regulation of heart rate / protein serine/threonine kinase activator activity / sarcomere / FCERI mediated Ca+2 mobilization / FCGR3A-mediated IL10 synthesis / VEGFR2 mediated vascular permeability / positive regulation of peptidyl-threonine phosphorylation / sarcoplasmic reticulum / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / VEGFR2 mediated cell proliferation / regulation of cytokinesis / muscle contraction / peptidylprolyl isomerase / peptidyl-prolyl cis-trans isomerase activity / Translocation of SLC2A4 (GLUT4) to the plasma membrane / spindle microtubule / calcium ion transmembrane transport / RAF activation / positive regulation of receptor signaling pathway via JAK-STAT
Similarity search - Function
: / Ryanodine receptor junctional solenoid repeat / Ryanodine receptor, SPRY domain 2 / 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 junctional solenoid repeat / Ryanodine receptor, SPRY domain 2 / 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. / SPRY domain / B30.2/SPRY domain superfamily / Domain in SPla and the RYanodine Receptor. / FKBP-type peptidyl-prolyl cis-trans isomerase domain profile. / FKBP-type peptidyl-prolyl cis-trans isomerase domain / FKBP-type peptidyl-prolyl cis-trans isomerase / 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. / Ion transport domain / Ion transport protein / EF-hand domain / 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
AuthorsMelville, Z. / Dridi, H. / Yuan, Q. / Reiken, S. / Anetta, W. / Liu, Y. / Clarke, O.B. / Marks, A.R.
Funding support United States, 6items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)R01HL145473 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)R01DK118240 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)R01HL142903 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)R01HL140934 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)R01AR070194 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)T32 HL120826 United States
CitationJournal: Structure / Year: 2022
Title: A drug and ATP binding site in type 1 ryanodine receptor.
Authors: Zephan Melville / Haikel Dridi / Qi Yuan / Steven Reiken / Anetta Wronska / Yang Liu / Oliver B Clarke / Andrew R Marks /
Abstract: The ryanodine receptor (RyR)/calcium release channel on the sarcoplasmic reticulum (SR) is required for excitation-contraction coupling in skeletal and cardiac muscle. Inherited mutations and stress- ...The ryanodine receptor (RyR)/calcium release channel on the sarcoplasmic reticulum (SR) is required for excitation-contraction coupling in skeletal and cardiac muscle. Inherited mutations and stress-induced post-translational modifications result in an SR Ca leak that causes skeletal myopathies, heart failure, and exercise-induced sudden death. A class of therapeutics known as Rycals prevent the RyR-mediated leak, are effective in preventing disease progression and restoring function in animal models, and are in clinical trials for patients with muscle and heart disorders. Using cryogenic-electron microscopy, we present a model of RyR1 with a 2.45-Å resolution before local refinement, revealing a binding site in the RY1&2 domain (3.10 Å local resolution), where the Rycal ARM210 binds cooperatively with ATP and stabilizes the closed state of RyR1.
History
DepositionFeb 15, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 18, 2022Provider: repository / Type: Initial release
Revision 1.1Jun 29, 2022Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed ..._citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Jul 20, 2022Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.page_first

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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
B: Ryanodine receptor 1
G: Ryanodine receptor 1
I: Ryanodine receptor 1
H: Peptidyl-prolyl cis-trans isomerase FKBP1A
J: Peptidyl-prolyl cis-trans isomerase FKBP1A
O: Peptidyl-prolyl cis-trans isomerase FKBP1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)2,392,46360
Polymers2,378,94312
Non-polymers13,52048
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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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 BL21(DE3) (bacteria) / 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: 11836.508 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 , 6 types, 48 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 / Adenosine triphosphate


Mass: 507.181 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / Feature type: SUBJECT OF INVESTIGATION / 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 / Caffeine (data page)


Mass: 194.191 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C8H10N4O2 / 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

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Details

Has ligand of interestY

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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: Ryanodine receptor 1 complex with calmodulin and calstabin-1
Type: COMPLEX / Entity ID: #1-#3 / Source: MULTIPLE SOURCES
Molecular weightValue: 2.31 MDa / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
11Oryctolagus cuniculus (rabbit)9986
21Homo sapiens (human)9606
Source (recombinant)Organism: Escherichia coli BL21(DE3) (bacteria)
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
110 mM2-[4-(2-Hydroxyethyl)piperazin-1-yl]ethane-1-sulfonic acidHEPES1
2400 mMSodium chlorideNaClSodium chloride1
30.5 mM(tris(2-carboxyethyl)phosphine)TCEP1
41 mMethylene glycol-bis-aminoethyl ether tetraacetic acidEGTA1
51 %Dimethyl trihydroxy-cholan-amido propyl azaniumyl propane sulfonateCHAPS1
60.5 mMaminoethyl benzenesulfonyl fluoride hydrochlorideAEBSF1
71 mMBenzamidine hydrochlorideBenzamidine1
80.01 %DipalmitoylphosphatidylcholineDOPC1
SpecimenConc.: 8.4 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: Quantifoil R0.6/1
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 4 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal magnification: 105000 X / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm / C2 aperture diameter: 100 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 2.5 sec. / Electron dose: 57.65 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 6862

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Processing

EM software
IDNameCategory
2Leginonimage acquisition
4cryoSPARCCTF correction
7Cootmodel fitting
9cryoSPARCinitial Euler assignment
10cryoSPARCfinal Euler assignment
11cryoSPARCclassification
12cryoSPARC3D reconstruction
13PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 333010
SymmetryPoint symmetry: C4 (4 fold cyclic)
3D reconstructionResolution: 2.45 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 153840 / Num. of class averages: 37 / Symmetry type: POINT

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