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- PDB-7ua5: Structure of dephosphorylated human RyR2 in the closed state -

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Basic information

Entry
Database: PDB / ID: 7ua5
TitleStructure of dephosphorylated human RyR2 in the closed state
Components
  • Peptidyl-prolyl cis-trans isomerase FKBP1B
  • Ryanodine receptor 2
KeywordsMEMBRANE PROTEIN / calcium channel
Function / homology
Function and homology information


junctional sarcoplasmic reticulum membrane / sarcoplasmic reticulum calcium ion transport / establishment of protein localization to endoplasmic reticulum / type B pancreatic cell apoptotic process / Purkinje myocyte to ventricular cardiac muscle cell signaling / calcium-induced calcium release activity / regulation of atrial cardiac muscle cell action potential / left ventricular cardiac muscle tissue morphogenesis / suramin binding / regulation of AV node cell action potential ...junctional sarcoplasmic reticulum membrane / sarcoplasmic reticulum calcium ion transport / establishment of protein localization to endoplasmic reticulum / type B pancreatic cell apoptotic process / Purkinje myocyte to ventricular cardiac muscle cell signaling / calcium-induced calcium release activity / regulation of atrial cardiac muscle cell action potential / left ventricular cardiac muscle tissue morphogenesis / suramin binding / regulation of AV node cell action potential / regulation of SA node cell action potential / cell communication by electrical coupling involved in cardiac conduction / regulation of ventricular cardiac muscle cell action potential / ventricular cardiac muscle cell action potential / positive regulation of sequestering of calcium ion / cyclic nucleotide binding / negative regulation of calcium-mediated signaling / embryonic heart tube morphogenesis / cardiac muscle hypertrophy / negative regulation of insulin secretion involved in cellular response to glucose stimulus / negative regulation of release of sequestered calcium ion into cytosol / neuronal action potential propagation / insulin secretion involved in cellular response to glucose stimulus / calcium ion transport into cytosol / ryanodine-sensitive calcium-release channel activity / response to caffeine / regulation of cardiac muscle contraction by calcium ion signaling / release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / response to redox state / 'de novo' protein folding / negative regulation of heart rate / response to muscle activity / FK506 binding / positive regulation of axon regeneration / protein kinase A regulatory subunit binding / protein kinase A catalytic subunit binding / cellular response to caffeine / positive regulation of the force of heart contraction / intracellularly gated calcium channel activity / smooth muscle contraction / response to vitamin E / detection of calcium ion / regulation of cardiac muscle contraction / regulation of cytosolic calcium ion concentration / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / smooth endoplasmic reticulum / calcium channel inhibitor activity / positive regulation of heart rate / T cell proliferation / Ion homeostasis / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / cardiac muscle contraction / release of sequestered calcium ion into cytosol / response to muscle stretch / sarcoplasmic reticulum membrane / calcium channel regulator activity / cellular response to epinephrine stimulus / calcium channel complex / protein maturation / regulation of heart rate / peptidyl-prolyl cis-trans isomerase activity / sarcoplasmic reticulum / RNA polymerase II CTD heptapeptide repeat P3 isomerase activity / RNA polymerase II CTD heptapeptide repeat P6 isomerase activity / establishment of localization in cell / peptidylprolyl isomerase / calcium-mediated signaling / sarcolemma / response to hydrogen peroxide / calcium channel activity / Stimuli-sensing channels / Z disc / intracellular calcium ion homeostasis / calcium ion transport / positive regulation of cytosolic calcium ion concentration / protein refolding / transmembrane transporter binding / response to hypoxia / calmodulin binding / signaling receptor binding / calcium ion binding / enzyme binding / protein-containing complex / identical protein binding / membrane / plasma membrane / 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 / 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 domain profile. / FKBP-type peptidyl-prolyl cis-trans isomerase / FKBP-type peptidyl-prolyl cis-trans isomerase domain / Peptidyl-prolyl cis-trans isomerase domain superfamily / EF-hand domain pair / 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 / Peptidyl-prolyl cis-trans isomerase FKBP1B / Ryanodine receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.83 Å
AuthorsMiotto, M.C. / Marks, A.R.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)R01HL145473 United States
CitationJournal: Sci Adv / Year: 2022
Title: Structural analyses of human ryanodine receptor type 2 channels reveal the mechanisms for sudden cardiac death and treatment.
Authors: Marco C Miotto / Gunnar Weninger / Haikel Dridi / Qi Yuan / Yang Liu / Anetta Wronska / Zephan Melville / Leah Sittenfeld / Steven Reiken / Andrew R Marks /
Abstract: Ryanodine receptor type 2 (RyR2) mutations have been linked to an inherited form of exercise-induced sudden cardiac death called catecholaminergic polymorphic ventricular tachycardia (CPVT). CPVT ...Ryanodine receptor type 2 (RyR2) mutations have been linked to an inherited form of exercise-induced sudden cardiac death called catecholaminergic polymorphic ventricular tachycardia (CPVT). CPVT results from stress-induced sarcoplasmic reticular Ca leak via the mutant RyR2 channels during diastole. We present atomic models of human wild-type (WT) RyR2 and the CPVT mutant RyR2-R2474S determined by cryo-electron microscopy with overall resolutions in the range of 2.6 to 3.6 Å, and reaching local resolutions of 2.25 Å, unprecedented for RyR2 channels. Under nonactivating conditions, the RyR2-R2474S channel is in a "primed" state between the closed and open states of WT RyR2, rendering it more sensitive to activation that results in stress-induced Ca leak. The Rycal drug ARM210 binds to RyR2-R2474S, reverting the primed state toward the closed state. Together, these studies provide a mechanism for CPVT and for the therapeutic actions of ARM210.
History
DepositionMar 11, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 3, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 23, 2024Group: Data collection / Refinement description / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_3d_fitting_list / em_admin / pdbx_entry_details / pdbx_initial_refinement_model / pdbx_modification_feature
Item: _em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id ..._em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id / _em_3d_fitting_list.source_name / _em_3d_fitting_list.type / _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Ryanodine receptor 2
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
B: Ryanodine receptor 2
C: Ryanodine receptor 2
D: Ryanodine receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)2,312,65820
Polymers2,308,3398
Non-polymers4,31912
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1(chain "B" and (resid 10 through 2577 or resid 2579...
d_2ens_1(chain "A" and (resid 10 through 2577 or resid 2579...
d_3ens_1(chain "C" and (resid 10 through 2577 or resid 2579...
d_4ens_1(chain "D" and (resid 10 through 2577 or resid 2579...
d_1ens_2chain "F"
d_2ens_2chain "E"
d_3ens_2chain "G"
d_4ens_2chain "H"

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg label comp-IDEnd label comp-IDLabel asym-IDLabel seq-ID
d_11ens_1GLUCYSI1 - 2351
d_12ens_1GLNLEUI2353 - 2594
d_13ens_1ALAASNI2596 - 4224
d_14ens_1ZNZNJ
d_15ens_1ATPATPK
d_16ens_1ATPATPL
d_21ens_1GLUCYSA1 - 2351
d_22ens_1GLNLEUA2353 - 2594
d_23ens_1ALAASNA2596 - 4224
d_24ens_1ZNZNB
d_25ens_1ATPATPC
d_26ens_1ATPATPD
d_31ens_1GLUCYSM1 - 2351
d_32ens_1GLNLEUM2353 - 2594
d_33ens_1ALAASNM2596 - 4224
d_34ens_1ZNZNN
d_35ens_1ATPATPO
d_36ens_1ATPATPP
d_41ens_1GLUCYSQ1 - 2351
d_42ens_1GLNLEUQ2353 - 2594
d_43ens_1ALAASNQ2596 - 4224
d_44ens_1ZNZNR
d_45ens_1ATPATPS
d_46ens_1ATPATPT
d_11ens_2GLYGLUF1 - 107
d_21ens_2GLYGLUE1 - 107
d_31ens_2GLYGLUG1 - 107
d_41ens_2GLYGLUH1 - 107

NCS ensembles :
ID
ens_1
ens_2

NCS oper:
IDCodeMatrixVector
1given(-0.00147831049119, -0.999998523146, 0.000876529657535), (0.999998675324, -0.00147771254148, 0.000682434178975), (-0.000681137912251, 0.000877537346024, 0.999999382989)428.6087573, 0.131546274349, -0.0748967784285
2given(0.0038617291212, 0.999991724179, -0.00128008638778), (-0.999992457443, 0.00386225668415, 0.000409915235599), (0.000414855865421, 0.00127849375105, 0.999999096674)-0.566821195828, 427.480492392, -0.468698142568
3given(-0.999986229715, -0.00426075271428, -0.00306371794203), (0.00426253213042, -0.999990750337, -0.000574507971087), (-0.00306124176728, -0.000587559256115, 0.999995141775)430.35301295, 427.288879108, 0.967202036084
4given(-0.00427870223249, -0.999968812588, 0.00663826465834), (0.999973402931, -0.00423932403302, 0.00593477574267), (-0.00590644889748, 0.00666348123817, 0.999960355154)428.190468547, 0.0817838316584, -0.360939548986
5given(0.00624451516896, 0.999980115102, 0.000880585682968), (-0.999977759298, 0.00624655839906, -0.00233696773417), (-0.0023424218937, -0.000865972867659, 0.99999688157)-1.54978981363, 427.195924163, 0.958400997603
6given(-0.999906494424, 0.00971388908963, -0.00962511129726), (-0.00978087662857, -0.999928102228, 0.00693720595631), (-0.00955703202396, 0.007030699315, 0.999929613726)427.391809071, 429.697609551, 0.636383691412

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Components

#1: Protein
Ryanodine receptor 2 / RYR-2 / RyR2 / hRYR-2 / Cardiac muscle ryanodine receptor / Cardiac muscle ryanodine receptor- ...RYR-2 / RyR2 / hRYR-2 / Cardiac muscle ryanodine receptor / Cardiac muscle ryanodine receptor-calcium release channel / Type 2 ryanodine receptor


Mass: 565286.125 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RYR2 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q92736
#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: 11798.501 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: P68106, peptidylprolyl isomerase
#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.: 8 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / Feature type: SUBJECT OF INVESTIGATION / Comment: ATP, energy-carrying molecule*YM
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-IDSource
1Complex of RyR2 and Calstabin-2COMPLEX#1-#20RECOMBINANT
2Ryanodine receptor 2COMPLEX#11RECOMBINANT
3Peptidyl-prolyl cis-trans isomerase FKBP1BCOMPLEX#21RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-IDCell
12Homo sapiens (human)9606HEK293
23Escherichia coli (E. coli)562
Buffer solutionpH: 7.4
Details: Xanthine was made fresh to avoid aggregation. Xanthine stock solution was 10 mM in NaOH 0.5 N.
Buffer component
IDConc.NameFormulaBuffer-ID
1230 mMNaClNaCl1
210 mMHEPESHEPES1
30.4 %CHAPSCHAPS1
41 mMEGTAEGTA1
50.5 mMTCEPTCEP1
60.001 %DOPCDOPC1
710 mMATPATP1
80.65 mMCaCl2CaCl21
90.5 mMXanthineXanthine1
SpecimenConc.: 1.6 mg/ml / Embedding 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: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1200 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 58 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

Software
NameVersionClassificationNB
phenix.real_space_refine1.19.2_4158refinement
PHENIX1.19.2_4158refinement
EM softwareName: cryoSPARC / Category: CTF correction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.83 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 90375 / Symmetry type: POINT
Atomic model buildingPDB-ID: 7U9Q

7u9q


Accession code: 7U9Q / Source name: PDB / Type: experimental model
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 107.25 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0031141628
ELECTRON MICROSCOPYf_angle_d0.7148191356
ELECTRON MICROSCOPYf_chiral_restr0.042620988
ELECTRON MICROSCOPYf_plane_restr0.007824588
ELECTRON MICROSCOPYf_dihedral_angle_d6.862718780
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2AELECTRON MICROSCOPYNCS constraints0.000706980943994
ens_1d_3GELECTRON MICROSCOPYNCS constraints0.0198487044156
ens_1d_4HELECTRON MICROSCOPYNCS constraints0.000707774396577
ens_2d_2BELECTRON MICROSCOPYNCS constraints0.000723223816837
ens_2d_3DELECTRON MICROSCOPYNCS constraints0.000713866216216
ens_2d_4EELECTRON MICROSCOPYNCS constraints0.000708926699605

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