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- PDB-6v6o: EGFR(T790M/V948R) in complex with LN2380 -

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Basic information

Entry
Database: PDB / ID: 6v6o
TitleEGFR(T790M/V948R) in complex with LN2380
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE/TRANSFERASE inhibitor / egfr / inhibitor / TRANSFERASE / TRANSFERASE-TRANSFERASE inhibitor complex
Function / homology
Function and homology information


response to hydroxyisoflavone / multivesicular body, internal vesicle lumen / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / positive regulation of protein kinase C activity / diterpenoid metabolic process / Shc-EGFR complex / ovulation cycle / Inhibition of Signaling by Overexpressed EGFR / epidermal growth factor receptor activity ...response to hydroxyisoflavone / multivesicular body, internal vesicle lumen / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / positive regulation of protein kinase C activity / diterpenoid metabolic process / Shc-EGFR complex / ovulation cycle / Inhibition of Signaling by Overexpressed EGFR / epidermal growth factor receptor activity / EGFR interacts with phospholipase C-gamma / positive regulation of mucus secretion / response to UV-A / epidermal growth factor binding / PLCG1 events in ERBB2 signaling / tongue development / midgut development / ERBB2-EGFR signaling pathway / hydrogen peroxide metabolic process / PTK6 promotes HIF1A stabilization / digestive tract morphogenesis / morphogenesis of an epithelial fold / ERBB2 Activates PTK6 Signaling / intracellular vesicle / Signaling by EGFR / response to cobalamin / transmembrane receptor protein tyrosine kinase activator activity / protein tyrosine kinase activator activity / negative regulation of epidermal growth factor receptor signaling pathway / Signaling by ERBB4 / eyelid development in camera-type eye / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / protein insertion into membrane / cerebral cortex cell migration / ERBB2 Regulates Cell Motility / Respiratory syncytial virus (RSV) attachment and entry / regulation of JNK cascade / : / PI3K events in ERBB2 signaling / positive regulation of cyclin-dependent protein serine/threonine kinase activity / negative regulation of mitotic cell cycle / hair follicle development / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / MAP kinase kinase kinase activity / embryonic placenta development / positive regulation of bone resorption / positive regulation of G1/S transition of mitotic cell cycle / GAB1 signalosome / salivary gland morphogenesis / peptidyl-tyrosine autophosphorylation / regulation of peptidyl-tyrosine phosphorylation / positive regulation of phosphorylation / positive regulation of glial cell proliferation / positive regulation of vasoconstriction / Signaling by ERBB2 / cellular response to epidermal growth factor stimulus / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / cellular response to cadmium ion / EGFR Transactivation by Gastrin / positive regulation of DNA repair / GRB2 events in ERBB2 signaling / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / transmembrane receptor protein tyrosine kinase activity / SHC1 events in ERBB2 signaling / positive regulation of synaptic transmission, glutamatergic / cellular response to dexamethasone stimulus / ossification / neurogenesis / regulation of ERK1 and ERK2 cascade / basal plasma membrane / neuron projection morphogenesis / positive regulation of superoxide anion generation / positive regulation of DNA replication / epithelial cell proliferation / Signal transduction by L1 / cellular response to estradiol stimulus / positive regulation of epithelial cell proliferation / NOTCH3 Activation and Transmission of Signal to the Nucleus / astrocyte activation / liver regeneration / positive regulation of protein localization to plasma membrane / EGFR downregulation / cellular response to amino acid stimulus / positive regulation of smooth muscle cell proliferation / Signaling by ERBB2 TMD/JMD mutants / positive regulation of MAP kinase activity / lung development / clathrin-coated endocytic vesicle membrane / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / epidermal growth factor receptor signaling pathway / negative regulation of protein catabolic process / receptor protein-tyrosine kinase / Downregulation of ERBB2 signaling / kinase binding / ruffle membrane / positive regulation of miRNA transcription / cell-cell adhesion
Similarity search - Function
: / Epidermal growth factor receptor transmembrane-juxtamembrane segment / Tyrosine protein kinase, EGF/ERB/XmrK receptor / Growth factor receptor domain 4 / Growth factor receptor domain IV / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily / Furin-like cysteine rich region / Receptor L domain ...: / Epidermal growth factor receptor transmembrane-juxtamembrane segment / Tyrosine protein kinase, EGF/ERB/XmrK receptor / Growth factor receptor domain 4 / Growth factor receptor domain IV / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily / Furin-like cysteine rich region / Receptor L domain / Furin-like repeat / Furin-like repeats / Growth factor receptor cysteine-rich domain superfamily / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-QQM / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsHeppner, D.E. / Eck, M.J.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R01CA201049 United States
CitationJournal: J.Med.Chem. / Year: 2020
Title: Structural Basis for EGFR Mutant Inhibition by Trisubstituted Imidazole Inhibitors.
Authors: Heppner, D.E. / Gunther, M. / Wittlinger, F. / Laufer, S.A. / Eck, M.J.
History
DepositionDec 5, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 22, 2020Provider: repository / Type: Initial release
Revision 1.1May 6, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Jul 15, 2020Group: Derived calculations
Category: pdbx_struct_assembly_gen / pdbx_struct_assembly_prop
Item: _pdbx_struct_assembly_gen.asym_id_list / _pdbx_struct_assembly_prop.value
Revision 1.3Feb 23, 2022Group: Database references / Experimental preparation / Category: database_2 / exptl_crystal
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _exptl_crystal.pdbx_mosaicity
Revision 1.4Oct 11, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id ..._struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
D: Epidermal growth factor receptor
A: Epidermal growth factor receptor
B: Epidermal growth factor receptor
C: Epidermal growth factor receptor
E: Epidermal growth factor receptor
F: Epidermal growth factor receptor
G: Epidermal growth factor receptor
H: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)303,33824
Polymers299,1388
Non-polymers4,20016
Water29,1481618
1
D: Epidermal growth factor receptor
E: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,8356
Polymers74,7852
Non-polymers1,0504
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3470 Å2
ΔGint-49 kcal/mol
Surface area26580 Å2
MethodPISA
2
A: Epidermal growth factor receptor
F: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,8356
Polymers74,7852
Non-polymers1,0504
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3530 Å2
ΔGint-47 kcal/mol
Surface area26090 Å2
MethodPISA
3
B: Epidermal growth factor receptor
hetero molecules

H: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,8356
Polymers74,7852
Non-polymers1,0504
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_444-x-1,y-1/2,-z-11
Buried area3380 Å2
ΔGint-46 kcal/mol
Surface area26470 Å2
MethodPISA
4
C: Epidermal growth factor receptor
hetero molecules

G: Epidermal growth factor receptor
hetero molecules


  • defined by author&software
  • 75.8 kDa, 2 polymers
Theoretical massNumber of molelcules
Total (without water)75,8356
Polymers74,7852
Non-polymers1,0504
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_544-x,y-1/2,-z-11
Buried area3440 Å2
ΔGint-46 kcal/mol
Surface area25660 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.550, 102.360, 173.569
Angle α, β, γ (deg.)90.000, 101.300, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and (resid 701 through 860 or resid 876...
21(chain B and (resid 701 through 860 or resid 876...
31(chain C and (resid 701 through 860 or resid 876...
41(chain D and (resid 701 through 860 or resid 876...
51(chain E and (resid 701 through 860 or resid 876...
61(chain F and (resid 701 through 860 or resid 876...
71(chain G and (resid 701 through 921 or resid 923...
81(chain H and (resid 701 through 860 or resid 876...

NCS domain segments:

Ens-ID: 1

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11GLNGLNLYSLYS(chain A and (resid 701 through 860 or resid 876...AB701 - 8606 - 165
12VALVALSERSER(chain A and (resid 701 through 860 or resid 876...AB876 - 921181 - 226
13GLNGLNCLCL(chain A and (resid 701 through 860 or resid 876...AB - K701 - 12016
14HISHISMETMET(chain A and (resid 701 through 860 or resid 876...AB988 - 1007293 - 312
15HOHHOHHOHHOH(chain A and (resid 701 through 860 or resid 876...AZ1301
21GLNGLNLYSLYS(chain B and (resid 701 through 860 or resid 876...BC701 - 8606 - 165
22VALVALSERSER(chain B and (resid 701 through 860 or resid 876...BC876 - 921181 - 226
23ILEILEGLNGLN(chain B and (resid 701 through 860 or resid 876...BC923 - 982228 - 287
24HISHISMETMET(chain B and (resid 701 through 860 or resid 876...BC988 - 1007293 - 312
25HOHHOHHOHHOH(chain B and (resid 701 through 860 or resid 876...BAA1301
31GLNGLNLYSLYS(chain C and (resid 701 through 860 or resid 876...CD701 - 8606 - 165
32VALVALSERSER(chain C and (resid 701 through 860 or resid 876...CD876 - 921181 - 226
33ILEILEGLNGLN(chain C and (resid 701 through 860 or resid 876...CD923 - 982228 - 287
34HISHISMETMET(chain C and (resid 701 through 860 or resid 876...CD988 - 1007293 - 312
35HOHHOHHOHHOH(chain C and (resid 701 through 860 or resid 876...CBA1301
41GLNGLNLYSLYS(chain D and (resid 701 through 860 or resid 876...DA701 - 8606 - 165
42VALVALSERSER(chain D and (resid 701 through 860 or resid 876...DA876 - 921181 - 226
43GLNGLNCLCL(chain D and (resid 701 through 860 or resid 876...DA - I701 - 12016
44HISHISMETMET(chain D and (resid 701 through 860 or resid 876...DA988 - 1007293 - 312
45HOHHOHHOHHOH(chain D and (resid 701 through 860 or resid 876...DY1301
51GLNGLNLYSLYS(chain E and (resid 701 through 860 or resid 876...EE701 - 8606 - 165
52VALVALSERSER(chain E and (resid 701 through 860 or resid 876...EE876 - 921181 - 226
53ILEILEGLNGLN(chain E and (resid 701 through 860 or resid 876...EE923 - 982228 - 287
54HISHISMETMET(chain E and (resid 701 through 860 or resid 876...EE988 - 1007293 - 312
55HOHHOHHOHHOH(chain E and (resid 701 through 860 or resid 876...ECA1301
61GLNGLNLYSLYS(chain F and (resid 701 through 860 or resid 876...FF701 - 8606 - 165
62VALVALSERSER(chain F and (resid 701 through 860 or resid 876...FF876 - 921181 - 226
63ILEILEGLNGLN(chain F and (resid 701 through 860 or resid 876...FF923 - 982228 - 287
64HISHISMETMET(chain F and (resid 701 through 860 or resid 876...FF988 - 1007293 - 312
65HOHHOHHOHHOH(chain F and (resid 701 through 860 or resid 876...FDA1301
71GLNGLNSERSER(chain G and (resid 701 through 921 or resid 923...GG701 - 9216 - 226
72ILEILEGLNGLN(chain G and (resid 701 through 921 or resid 923...GG923 - 982228 - 287
73HISHISMETMET(chain G and (resid 701 through 921 or resid 923...GG988 - 1007293 - 312
74QQMQQMQQMQQM(chain G and (resid 701 through 921 or resid 923...GU1301
81GLNGLNLYSLYS(chain H and (resid 701 through 860 or resid 876...HH701 - 8606 - 165
82VALVALSERSER(chain H and (resid 701 through 860 or resid 876...HH876 - 921181 - 226
83ILEILEMETMET(chain H and (resid 701 through 860 or resid 876...HH923 - 1007228 - 312
84HOHHOHHOHHOH(chain H and (resid 701 through 860 or resid 876...HFA1301

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Components

#1: Protein
Epidermal growth factor receptor / Proto-oncogene c-ErbB-1 / Receptor tyrosine-protein kinase erbB-1


Mass: 37392.285 Da / Num. of mol.: 8
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EGFR, ERBB, ERBB1, HER1 / Plasmid: pEX / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P00533, receptor protein-tyrosine kinase
#2: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Cl
#3: Chemical
ChemComp-QQM / N-[3-({4-[4-(4-fluorophenyl)-2-(3-hydroxypropyl)-1H-imidazol-5-yl]pyridin-2-yl}amino)-4-methoxyphenyl]propanamide


Mass: 489.541 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C27H28FN5O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1618 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.08 Å3/Da / Density % sol: 40.83 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 5.5 / Details: 0.1 M Bis-Tris, 25% PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.9792 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Aug 18, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9792 Å / Relative weight: 1
ReflectionResolution: 2.1→69.87 Å / Num. obs: 141083 / % possible obs: 98.8 % / Redundancy: 7 % / CC1/2: 0.996 / Rmerge(I) obs: 0.115 / Rpim(I) all: 0.047 / Rrim(I) all: 0.124 / Net I/σ(I): 11
Reflection shell

Diffraction-ID: 1 / Redundancy: 7 %

Resolution (Å)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.1-2.150.62972819103740.9450.2530.6793.998.8
9.39-69.830.0691184416860.9950.0280.07520.799.7

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
Aimless0.7.4data scaling
PDB_EXTRACT3.25data extraction
xia2data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5d41

5d41


Resolution: 2.1→69.83 Å / SU ML: 0.22 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 25.03
RfactorNum. reflection% reflection
Rfree0.2206 7020 4.99 %
Rwork0.195 --
obs0.1963 140814 98.45 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 101.98 Å2 / Biso mean: 31.3862 Å2 / Biso min: 9.29 Å2
Refinement stepCycle: final / Resolution: 2.1→69.83 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms19521 0 296 1618 21435
Biso mean--24.79 36.76 -
Num. residues----2427
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A10139X-RAY DIFFRACTION12.972TORSIONAL
12B10139X-RAY DIFFRACTION12.972TORSIONAL
13C10139X-RAY DIFFRACTION12.972TORSIONAL
14D10139X-RAY DIFFRACTION12.972TORSIONAL
15E10139X-RAY DIFFRACTION12.972TORSIONAL
16F10139X-RAY DIFFRACTION12.972TORSIONAL
17G10139X-RAY DIFFRACTION12.972TORSIONAL
18H10139X-RAY DIFFRACTION12.972TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 30

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.1-2.120.29532360.24254297453396
2.12-2.150.30032400.23444468470899
2.15-2.180.29392350.22784441467698
2.18-2.20.27582390.22074425466499
2.2-2.230.28552350.22544477471299
2.23-2.260.23862350.2224408464399
2.26-2.290.27332540.21874450470499
2.29-2.330.25551950.21764483467899
2.33-2.370.26772520.2184434468699
2.37-2.40.26972190.22144501472099
2.4-2.450.2642190.22164460467999
2.45-2.490.25782070.22264355456296
2.49-2.540.25522160.21884110432692
2.54-2.590.25482510.21734477472899
2.59-2.650.24252430.211745044747100
2.65-2.710.25972320.211144974729100
2.71-2.780.25282370.208145274764100
2.78-2.850.25162170.207445344751100
2.85-2.930.22642280.208244754703100
2.93-3.030.24172400.207245274767100
3.03-3.140.21332150.201345454760100
3.14-3.260.2342140.199645614775100
3.26-3.410.22412350.192245394774100
3.41-3.590.20692200.185445054725100
3.59-3.820.18532370.172545344771100
3.82-4.110.16492320.16224502473499
4.11-4.520.15932870.15464457474499
4.52-5.180.17732220.16634167438991
5.18-6.520.1962620.188645634825100
6.53-69.870.19652660.17964571483799

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