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- PDB-8set: Cryo-EM Structure of RyR1 + cAMP -

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Basic information

Entry
Database: PDB / ID: 8set
TitleCryo-EM Structure of RyR1 + cAMP
Components
  • Glutathione S-transferase class-mu 26 kDa isozyme,Peptidyl-prolyl cis-trans isomerase FKBP1B
  • Ryanodine receptor 1
KeywordsTRANSPORT PROTEIN / Calcium ion channel / skeletal muscle / nucleotide / homotetramer
Function / homology
Function and homology information


negative regulation of calcium-mediated signaling / ATP-gated ion channel activity / ryanodine-sensitive calcium-release channel activity / negative regulation of release of sequestered calcium ion into cytosol / terminal cisterna / ryanodine receptor complex / response to redox state / release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / ossification involved in bone maturation / negative regulation of heart rate ...negative regulation of calcium-mediated signaling / ATP-gated ion channel activity / ryanodine-sensitive calcium-release channel activity / negative regulation of release of sequestered calcium ion into cytosol / terminal cisterna / ryanodine receptor complex / response to redox state / release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / ossification involved in bone maturation / negative regulation of heart rate / skin development / cellular response to caffeine / FK506 binding / 'de novo' protein folding / outflow tract morphogenesis / organelle membrane / smooth endoplasmic reticulum / glutathione transferase / intracellularly gated calcium channel activity / glutathione transferase activity / regulation of ryanodine-sensitive calcium-release channel activity / toxic substance binding / skeletal muscle fiber development / voltage-gated calcium channel activity / calcium channel inhibitor activity / release of sequestered calcium ion into cytosol / 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 / muscle contraction / cellular response to calcium ion / calcium channel complex / sarcoplasmic reticulum membrane / glutathione metabolic process / calcium-mediated signaling / peptidylprolyl isomerase / sarcoplasmic reticulum / striated muscle contraction / peptidyl-prolyl cis-trans isomerase activity / calcium channel regulator activity / protein maturation / protein refolding / sarcolemma / intracellular calcium ion homeostasis / Stimuli-sensing channels / Z disc / calcium ion transmembrane transport / calcium channel activity / disordered domain specific binding / protein folding / protein homotetramerization / transmembrane transporter binding / calmodulin binding / signaling receptor binding / calcium ion binding / ATP binding / membrane / identical protein binding / cytoplasm
Similarity search - Function
Glutathione S-transferase, C-terminal 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 ...Glutathione S-transferase, C-terminal 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 / Glutathione S-transferase, N-terminal domain / Glutathione S-transferase, C-terminal / Glutathione transferase family / Glutathione S-transferase, C-terminal-like / Soluble glutathione S-transferase C-terminal domain profile. / Soluble glutathione S-transferase N-terminal domain profile. / Glutathione S-transferase, N-terminal / 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 / Glutathione S-transferase, C-terminal domain superfamily / Peptidyl-prolyl cis-trans isomerase domain superfamily / Ion transport domain / Ion transport protein / EF-hand domain pair / Concanavalin A-like lectin/glucanase domain superfamily / Thioredoxin-like superfamily
Similarity search - Domain/homology
ADENOSINE-3',5'-CYCLIC-MONOPHOSPHATE / Glutathione S-transferase class-mu 26 kDa isozyme / Ryanodine receptor 1 / Peptidyl-prolyl cis-trans isomerase FKBP1B
Similarity search - Component
Biological speciesHomo sapiens (human)
Oryctolagus cuniculus (rabbit)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.42 Å
AuthorsCholak, S. / Saville, J.W. / Zhu, X. / Berezuk, A.M. / Tuttle, K.S. / Haji-Ghassemi, O. / Van Petegem, F. / Subramaniam, S.
Funding support Canada, 2items
OrganizationGrant numberCountry
Canada Excellence Research Chair Award Canada
Canadian Institutes of Health Research (CIHR) Canada
CitationJournal: Structure / Year: 2023
Title: Allosteric modulation of ryanodine receptor RyR1 by nucleotide derivatives.
Authors: Spencer Cholak / James W Saville / Xing Zhu / Alison M Berezuk / Katharine S Tuttle / Omid Haji-Ghassemi / Francisco J Alvarado / Filip Van Petegem / Sriram Subramaniam /
Abstract: The coordinated release of Ca from the sarcoplasmic reticulum (SR) is critical for excitation-contraction coupling. This release is facilitated by ryanodine receptors (RyRs) that are embedded in the ...The coordinated release of Ca from the sarcoplasmic reticulum (SR) is critical for excitation-contraction coupling. This release is facilitated by ryanodine receptors (RyRs) that are embedded in the SR membrane. In skeletal muscle, activity of RyR1 is regulated by metabolites such as ATP, which upon binding increase channel open probability (P). To obtain structural insights into the mechanism of RyR1 priming by ATP, we determined several cryo-EM structures of RyR1 bound individually to ATP-γ-S, ADP, AMP, adenosine, adenine, and cAMP. We demonstrate that adenine and adenosine bind RyR1, but AMP is the smallest ATP derivative capable of inducing long-range (>170 Å) structural rearrangements associated with channel activation, establishing a structural basis for key binding site interactions that are the threshold for triggering quaternary structural changes. Our finding that cAMP also induces these structural changes and results in increased channel opening suggests its potential role as an endogenous modulator of RyR1 conductance.
History
DepositionApr 10, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 24, 2023Provider: repository / Type: Initial release
Revision 1.1May 31, 2023Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Jul 19, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Nov 13, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Ryanodine receptor 1
B: Ryanodine receptor 1
C: Ryanodine receptor 1
D: Ryanodine receptor 1
E: Glutathione S-transferase class-mu 26 kDa isozyme,Peptidyl-prolyl cis-trans isomerase FKBP1B
F: Glutathione S-transferase class-mu 26 kDa isozyme,Peptidyl-prolyl cis-trans isomerase FKBP1B
G: Glutathione S-transferase class-mu 26 kDa isozyme,Peptidyl-prolyl cis-trans isomerase FKBP1B
H: Glutathione S-transferase class-mu 26 kDa isozyme,Peptidyl-prolyl cis-trans isomerase FKBP1B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)2,425,39316
Polymers2,423,8158
Non-polymers1,5788
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails (eV)
d_1ens_1(chain "A" and (resid 11 through 1230 or resid 1232...
d_2ens_1(chain "B" and (resid 11 through 1230 or resid 1232...
d_3ens_1(chain "C" and (resid 11 through 1230 or resid 1232...
d_4ens_1(chain "D" and (resid 11 through 1230 or resid 1232...
d_1ens_2chain "H"
d_2ens_2chain "F"
d_3ens_2chain "G"
d_4ens_2chain "E"

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
d_11ens_1VALVALMETMETAA11 - 123011 - 1230
d_12ens_1ARGARGTHRTHRAA1232 - 17421232 - 1742
d_13ens_1ALAALASERSERAA1744 - 20991744 - 2099
d_14ens_1METMETMETMETAA2101 - 22672101 - 2267
d_15ens_1GLYGLYLEULEUAA2269 - 23682269 - 2368
d_16ens_1GLYGLYLEULEUAA2370 - 25832370 - 2583
d_17ens_1THRTHRCYSCYSAA2585 - 26112585 - 2611
d_18ens_1TYRTYRARGARGAA2613 - 28692613 - 2869
d_19ens_1LEULEUALAALAAA2871 - 34212871 - 3421
d_110ens_1TRPTRPSERSERAA3423 - 50373423 - 5037
d_111ens_1CMPCMPCMPCMPAI5101
d_21ens_1VALVALMETMETBB11 - 123011 - 1230
d_22ens_1ARGARGTHRTHRBB1232 - 17421232 - 1742
d_23ens_1ALAALASERSERBB1744 - 20991744 - 2099
d_24ens_1METMETMETMETBB2101 - 22672101 - 2267
d_25ens_1GLYGLYLEULEUBB2269 - 23682269 - 2368
d_26ens_1GLYGLYLEULEUBB2370 - 25832370 - 2583
d_27ens_1THRTHRCYSCYSBB2585 - 26112585 - 2611
d_28ens_1TYRTYRARGARGBB2613 - 28692613 - 2869
d_29ens_1LEULEUALAALABB2871 - 34212871 - 3421
d_210ens_1TRPTRPSERSERBB3423 - 50373423 - 5037
d_211ens_1CMPCMPCMPCMPBK5101
d_31ens_1VALVALMETMETCC11 - 123011 - 1230
d_32ens_1ARGARGTHRTHRCC1232 - 17421232 - 1742
d_33ens_1ALAALASERSERCC1744 - 20991744 - 2099
d_34ens_1METMETMETMETCC2101 - 22672101 - 2267
d_35ens_1GLYGLYLEULEUCC2269 - 23682269 - 2368
d_36ens_1GLYGLYLEULEUCC2370 - 25832370 - 2583
d_37ens_1THRTHRCYSCYSCC2585 - 26112585 - 2611
d_38ens_1TYRTYRARGARGCC2613 - 28692613 - 2869
d_39ens_1LEULEUALAALACC2871 - 34212871 - 3421
d_310ens_1TRPTRPSERSERCC3423 - 50373423 - 5037
d_311ens_1CMPCMPCMPCMPCM5101
d_41ens_1VALVALMETMETDD11 - 123011 - 1230
d_42ens_1ARGARGTHRTHRDD1232 - 17421232 - 1742
d_43ens_1ALAALASERSERDD1744 - 20991744 - 2099
d_44ens_1METMETMETMETDD2101 - 22672101 - 2267
d_45ens_1GLYGLYLEULEUDD2269 - 23682269 - 2368
d_46ens_1GLYGLYLEULEUDD2370 - 25832370 - 2583
d_47ens_1THRTHRCYSCYSDD2585 - 26112585 - 2611
d_48ens_1TYRTYRARGARGDD2613 - 28692613 - 2869
d_49ens_1LEULEUALAALADD2871 - 34212871 - 3421
d_410ens_1TRPTRPSERSERDD3423 - 50373423 - 5037
d_411ens_1CMPCMPCMPCMPDO5101
d_11ens_2GLYGLYGLUGLUHH1 - 107244 - 350
d_21ens_2GLYGLYGLUGLUFF1 - 107244 - 350
d_31ens_2GLYGLYGLUGLUGG1 - 107244 - 350
d_41ens_2GLYGLYGLUGLUEE1 - 107244 - 350

NCS ensembles :
ID
ens_1
ens_2

NCS oper:
IDCodeMatrixVector
1given(-0.000538100067483, -0.99999807173, 0.00188864615841), (0.999999761189, -0.000538918107808, -0.000432653647902), (0.000433670639243, 0.00188841289642, 0.999998122911)514.773725872, 0.274393054659, -0.617540141845
2given(-0.999999761778, 0.000539901788642, 0.000430057818226), (-0.000539087356828, -0.999998065534, 0.00189164288998), (0.000431078287673, 0.00189141060062, 0.999998118367)514.926017521, 514.773004855, -0.618047067445
3given(0.000539738096977, 0.999998067811, -0.00189025295991), (-0.999999760786, 0.000540554736311, 0.000431542238281), (0.00043256318965, 0.00189001958795, 0.999998120356)0.426453590718, 514.925373834, -0.617687378169
4given(-1, -2.320885E-7, 2.13685206027E-7), (2.32088502588E-7, -1, 1.21104005247E-8), (2.13685203216E-7, 1.21104501186E-8, 1)515.199999197, 515.199921872, -8.39149507215E-5
5given(5.01779452655E-7, 1, 4.31335286204E-7), (-1, 5.01779551687E-7, -2.2980575953E-7), (-2.29805975965E-7, -4.31335170892E-7, 1)-0.000313046820565, 515.199903979, 0.000227922610122
6given(-7.80473837336E-7, -1, -6.2292879994E-7), (1, -7.80473498496E-7, -5.43976847979E-7), (5.439763618E-7, -6.229292245E-7, 1)515.200481065, 0.000419720514628, -4.47244332236E-6

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Components

#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
Glutathione S-transferase class-mu 26 kDa isozyme,Peptidyl-prolyl cis-trans isomerase FKBP1B / GST 26 / Sj26 antigen / SjGST / PPIase FKBP1B / 12.6 kDa FK506-binding protein / 12.6 kDa FKBP / ...GST 26 / Sj26 antigen / SjGST / PPIase FKBP1B / 12.6 kDa FK506-binding protein / 12.6 kDa FKBP / FKBP-12.6 / FK506-binding protein 1B / FKBP-1B / Immunophilin FKBP12.6 / Rotamase / h-FKBP-12


Mass: 40045.012 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 (E. coli)
References: UniProt: P08515, UniProt: P68106, glutathione transferase, peptidylprolyl isomerase
#3: Chemical
ChemComp-CMP / ADENOSINE-3',5'-CYCLIC-MONOPHOSPHATE / CYCLIC AMP / CAMP


Mass: 329.206 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C10H12N5O6P / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
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 FKBP12.6 / Type: COMPLEX / Entity ID: #1-#2 / Source: MULTIPLE SOURCES
Source (natural)Organism: Oryctolagus cuniculus (rabbit)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 283.15 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 magnification: 96000 X / Nominal defocus max: 2000 nm / Nominal defocus min: 500 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 40 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

Software
NameVersionClassificationNB
phenix.real_space_refine1.20.1_4487refinement
PHENIX1.20.1_4487refinement
EM softwareName: EPU / Version: 3.3 / Category: image acquisition
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.42 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 206618 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 220.82 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0056146316
ELECTRON MICROSCOPYf_angle_d1.0327198204
ELECTRON MICROSCOPYf_chiral_restr0.058621788
ELECTRON MICROSCOPYf_plane_restr0.007325764
ELECTRON MICROSCOPYf_dihedral_angle_d14.780954628
Refine LS restraints NCS
Ens-IDDom-IDAsym-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2AAELECTRON MICROSCOPYNCS constraints9.69058032478E-10
ens_1d_3AAELECTRON MICROSCOPYNCS constraints2.00700928262E-11
ens_1d_4AAELECTRON MICROSCOPYNCS constraints1.47936625013E-12
ens_2d_2HHELECTRON MICROSCOPYNCS constraints1.94682102794E-13
ens_2d_3HHELECTRON MICROSCOPYNCS constraints3.97493744515E-11
ens_2d_4HHELECTRON MICROSCOPYNCS constraints5.17064763946E-13

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