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- PDB-7ua9: Structure of dephosphorylated human RyR2 in the open state -

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Basic information

Entry
Database: PDB / ID: 7ua9
TitleStructure of dephosphorylated human RyR2 in the open 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 / suramin binding / establishment of protein localization to endoplasmic reticulum / type B pancreatic cell apoptotic process / Purkinje myocyte to ventricular cardiac muscle cell signaling / regulation of SA node cell action potential / regulation of atrial cardiac muscle cell action potential / left ventricular cardiac muscle tissue morphogenesis / regulation of AV node cell action potential / positive regulation of ATPase-coupled calcium transmembrane transporter activity ...junctional sarcoplasmic reticulum membrane / suramin binding / establishment of protein localization to endoplasmic reticulum / type B pancreatic cell apoptotic process / Purkinje myocyte to ventricular cardiac muscle cell signaling / regulation of SA node cell action potential / regulation of atrial cardiac muscle cell action potential / left ventricular cardiac muscle tissue morphogenesis / regulation of AV node cell action potential / positive regulation of ATPase-coupled calcium transmembrane transporter activity / calcium-induced calcium release activity / sarcoplasmic reticulum calcium ion transport / ventricular cardiac muscle cell action potential / regulation of ventricular cardiac muscle cell action potential / positive regulation of sequestering of calcium ion / cyclic nucleotide binding / embryonic heart tube morphogenesis / negative regulation of release of sequestered calcium ion into cytosol / negative regulation of insulin secretion involved in cellular response to glucose stimulus / regulation of cardiac muscle contraction by calcium ion signaling / cardiac muscle hypertrophy / ryanodine-sensitive calcium-release channel activity / neuronal action potential propagation / insulin secretion involved in cellular response to glucose stimulus / release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / response to muscle activity / calcium ion transport into cytosol / response to caffeine / cell communication by electrical coupling involved in cardiac conduction / response to redox state / protein maturation by protein folding / 'de novo' protein folding / negative regulation of heart rate / negative regulation of phosphoprotein phosphatase activity / positive regulation of heart rate / FK506 binding / positive regulation of axon regeneration / cellular response to caffeine / protein kinase A regulatory subunit binding / smooth endoplasmic reticulum / intracellularly gated calcium channel activity / protein kinase A catalytic subunit binding / positive regulation of the force of heart contraction / : / detection of calcium ion / smooth muscle contraction / striated muscle contraction / negative regulation of ryanodine-sensitive calcium-release channel activity / response to vitamin E / regulation of cardiac muscle contraction / calcium channel inhibitor activity / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / protein peptidyl-prolyl isomerization / T cell proliferation / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / release of sequestered calcium ion into cytosol / Ion homeostasis / regulation of ryanodine-sensitive calcium-release channel activity / cardiac muscle contraction / sarcoplasmic reticulum membrane / cellular response to epinephrine stimulus / calcium channel complex / regulation of cytosolic calcium ion concentration / response to muscle stretch / regulation of heart rate / sarcoplasmic reticulum / peptidylprolyl isomerase / peptidyl-prolyl cis-trans isomerase activity / establishment of localization in cell / calcium-mediated signaling / sarcolemma / response to hydrogen peroxide / calcium channel activity / Stimuli-sensing channels / intracellular calcium ion homeostasis / Z disc / : / 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 / membrane / identical protein binding / plasma membrane / cytosol / cytoplasm
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 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 / XANTHINE / Peptidyl-prolyl cis-trans isomerase FKBP1B / Ryanodine receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.59 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)2,313,42628
Polymers2,308,3398
Non-polymers5,08820
Water0
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 "C" and (resid 10 through 2577 or resid 2579...
d_2ens_1(chain "B" and (resid 10 through 2577 or resid 2579...
d_3ens_1(chain "A" and (resid 10 through 2577 or resid 2579...
d_4ens_1(chain "D" and (resid 10 through 2577 or resid 2579...
d_1ens_2chain "G"
d_2ens_2chain "E"
d_3ens_2chain "F"
d_4ens_2chain "H"

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg label comp-IDEnd label comp-IDLabel asym-IDLabel seq-ID
d_11ens_1GLUCYSQ1 - 2351
d_12ens_1GLNLEUQ2353 - 2594
d_13ens_1ALAASNQ2596 - 4224
d_14ens_1ZNZNR
d_15ens_1ATPATPS
d_16ens_1CACAT
d_17ens_1XANXANU
d_18ens_1ATPATPV
d_21ens_1GLUCYSK1 - 2351
d_22ens_1GLNLEUK2353 - 2594
d_23ens_1ALAASNK2596 - 4224
d_24ens_1ZNZNL
d_25ens_1ATPATPM
d_26ens_1CACAN
d_27ens_1XANXANO
d_28ens_1ATPATPP
d_31ens_1GLUCYSE1 - 2351
d_32ens_1GLNLEUE2353 - 2594
d_33ens_1ALAASNE2596 - 4224
d_34ens_1ZNZNF
d_35ens_1ATPATPG
d_36ens_1CACAH
d_37ens_1XANXANI
d_38ens_1ATPATPJ
d_41ens_1GLUCYSW1 - 2351
d_42ens_1GLNLEUW2353 - 2594
d_43ens_1ALAASNW2596 - 4224
d_44ens_1ZNZNX
d_45ens_1ATPATPY
d_46ens_1CACAZ
d_47ens_1XANXANAA
d_48ens_1ATPATPBA
d_11ens_2GLYGLUC1 - 107
d_21ens_2GLYGLUA1 - 107
d_31ens_2GLYGLUB1 - 107
d_41ens_2GLYGLUD1 - 107

NCS ensembles :
ID
ens_1
ens_2

NCS oper:
IDCodeMatrixVector
1given(-0.00576957110622, -0.999973115194, 0.00452558712347), (0.999971745282, -0.00579125358826, -0.00479270475271), (0.00481878472444, 0.00449780740342, 0.999978274285)428.620733691, 2.11945184958, -1.93764053577
2given(-0.999999224682, 0.00108623028217, -0.000608882766955), (-0.0010883567486, -0.99999327213, 0.00350302346244), (-0.000605073580307, 0.00350368342815, 0.999993679024)428.186798396, 427.933311648, -0.6067460088
3given(-0.0013540736481, 0.999989487609, -0.00438077123975), (-0.999987690034, -0.00133313359474, 0.00477938655854), (0.00477349616245, 0.00438718895399, 0.999978982933)1.64639473148, 427.237800596, -1.78973301433
4given(-0.999994100677, -0.00205496446189, 0.00275240498511), (0.00206386781547, -0.999992634902, 0.00323582947546), (0.0027457351988, 0.00324149098631, 0.999990976796)428.042297684, 426.99096984, -1.53108891376
5given(-0.000402506604866, -0.999996788019, 0.00250238690805), (0.999995777242, -0.00040970581029, -0.00287708871945), (0.00287810472075, 0.00250121829387, 0.999992730184)427.611315152, 1.15224300196, -1.13236349485
6given(0.0153779200625, 0.999825288217, -0.0106260348622), (-0.999850068994, 0.0154611659718, 0.00779691479348), (0.00795984346921, 0.0105045413577, 0.999913143979)-2.34532370534, 423.971687787, -3.33471247731

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Components

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Protein , 2 types, 8 molecules EFGHABCD

#1: 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
#2: 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

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Non-polymers , 4 types, 20 molecules

#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 / 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
#5: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Ca / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical
ChemComp-XAN / XANTHINE / Xanthine


Mass: 152.111 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C5H4N4O2 / Feature type: SUBJECT OF INVESTIGATION

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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

Component
IDNameTypeEntity IDParent-IDSource
1Complex of RyR2 and Calstabin-2COMPLEX#1-#20RECOMBINANT
2Ryanodine receptor 2COMPLEX#21RECOMBINANT
3Peptidyl-prolyl cis-trans isomerase FKBP1BCOMPLEX#11RECOMBINANT
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 mMNaClSodium chlorideNaClSodium chloride1
210 mMHEPESHEPES1
30.4 %CHAPSCHAPS1
41 mMEGTAEGTA1
50.5 mMTCEPTCEP1
60.001 %DOPCDOPC1
710 mMATPAdenosine triphosphateATPAdenosine triphosphate1
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 FIELDBright-field microscopy / 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: 3.59 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 36491 / Symmetry type: POINT
Atomic model buildingPDB-ID: 7U9Q

7u9q

RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 135.19 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0099141676
ELECTRON MICROSCOPYf_angle_d0.8179191424
ELECTRON MICROSCOPYf_chiral_restr0.042620988
ELECTRON MICROSCOPYf_plane_restr0.006124592
ELECTRON MICROSCOPYf_dihedral_angle_d5.836318780
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2FELECTRON MICROSCOPYNCS constraints0.000706232094405
ens_1d_3EELECTRON MICROSCOPYNCS constraints0.000707720586664
ens_1d_4HELECTRON MICROSCOPYNCS constraints0.000707173029346
ens_2d_2AELECTRON MICROSCOPYNCS constraints0.000721083013293
ens_2d_3BELECTRON MICROSCOPYNCS constraints0.000698500210307
ens_2d_4DELECTRON MICROSCOPYNCS constraints0.000711769074172

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