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- PDB-5j9z: EGFR-T790M in complex with pyrazolopyrimidine inhibitor 1a -

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Basic information

Entry
Database: PDB / ID: 5j9z
TitleEGFR-T790M in complex with pyrazolopyrimidine inhibitor 1a
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / tyrosine kinase / covalent inhibitor / drug resistance
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 / regulation of nitric-oxide synthase activity / morphogenesis of an epithelial fold / ERBB2 Activates PTK6 Signaling / intracellular vesicle / Signaling by EGFR / response to cobalamin / negative regulation of epidermal growth factor receptor signaling pathway / transmembrane receptor protein tyrosine kinase activator activity / protein tyrosine kinase activator activity / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / Signaling by ERBB4 / protein insertion into membrane / eyelid development in camera-type eye / cerebral cortex cell migration / ERBB2 Regulates Cell Motility / regulation of JNK cascade / activation of phospholipase C activity / PI3K events in ERBB2 signaling / positive regulation of cyclin-dependent protein serine/threonine kinase activity / negative regulation of mitotic cell cycle / hair follicle development / MAP kinase kinase kinase activity / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / positive regulation of G1/S transition of mitotic cell cycle / embryonic placenta development / positive regulation of DNA replication / positive regulation of bone resorption / GAB1 signalosome / positive regulation of nitric oxide mediated signal transduction / salivary gland morphogenesis / regulation of peptidyl-tyrosine phosphorylation / peptidyl-tyrosine autophosphorylation / positive regulation of vasoconstriction / positive regulation of glial cell proliferation / positive regulation of phosphorylation / Signaling by ERBB2 / cellular response to epidermal growth factor stimulus / cellular response to cadmium ion / positive regulation of DNA repair / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / GRB2 events in ERBB2 signaling / neurogenesis / transmembrane receptor protein tyrosine kinase activity / ossification / cellular response to dexamethasone stimulus / SHC1 events in ERBB2 signaling / positive regulation of synaptic transmission, glutamatergic / basal plasma membrane / regulation of ERK1 and ERK2 cascade / neuron projection morphogenesis / positive regulation of superoxide anion generation / Signal transduction by L1 / epithelial cell proliferation / cellular response to estradiol stimulus / liver regeneration / NOTCH3 Activation and Transmission of Signal to the Nucleus / positive regulation of epithelial cell proliferation / astrocyte activation / cellular response to amino acid stimulus / positive regulation of protein localization to plasma membrane / EGFR downregulation / clathrin-coated endocytic vesicle membrane / lung development / positive regulation of smooth muscle cell proliferation / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII / positive regulation of MAP kinase activity / Signaling by ERBB2 ECD mutants / epidermal growth factor receptor signaling pathway / Signaling by ERBB2 KD Mutants / negative regulation of protein catabolic process / cell-cell adhesion / receptor protein-tyrosine kinase / ruffle membrane / Downregulation of ERBB2 signaling / kinase binding
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-6HJ / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsBecker, C. / Engel, J. / Rauh, D.
CitationJournal: Angew.Chem.Int.Ed.Engl. / Year: 2016
Title: Insight into the Inhibition of Drug-Resistant Mutants of the Receptor Tyrosine Kinase EGFR.
Authors: Engel, J. / Becker, C. / Lategahn, J. / Keul, M. / Ketzer, J. / Muhlenberg, T. / Kollipara, L. / Schultz-Fademrecht, C. / Zahedi, R.P. / Bauer, S. / Rauh, D.
History
DepositionApr 11, 2016Deposition site: RCSB / Processing site: PDBE
Revision 1.0Aug 17, 2016Provider: repository / Type: Initial release
Revision 1.1Sep 7, 2016Group: Database references
Revision 1.2Feb 20, 2019Group: Advisory / Data collection / Derived calculations
Category: database_PDB_remark / pdbx_data_processing_status ...database_PDB_remark / pdbx_data_processing_status / pdbx_validate_symm_contact / struct_conn
Item: _database_PDB_remark.text
Revision 1.3Jan 10, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,5512
Polymers37,1491
Non-polymers4011
Water37821
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area14890 Å2
MethodPISA
Unit cell
Length a, b, c (Å)146.460, 146.460, 146.460
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number197
Space group name H-MI23

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Components

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


Mass: 37149.039 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EGFR, ERBB, ERBB1, HER1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P00533, receptor protein-tyrosine kinase
#2: Chemical ChemComp-6HJ / (R)-1-(3-(4-amino-3-(1-methyl-1H-indol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one


Mass: 401.464 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H23N7O
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 21 / Source method: isolated from a natural source / Formula: H2O

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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: 3.39 Å3/Da / Density % sol: 63.75 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 100 mM MES, 900 mM - 1100 mM Na/K-tartrate / PH range: 7.0-7.3

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.91884 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Apr 16, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91884 Å / Relative weight: 1
ReflectionResolution: 2.5→46.31 Å / Num. obs: 18225 / % possible obs: 100 % / Observed criterion σ(I): -3 / Redundancy: 40.65 % / Biso Wilson estimate: 58.003 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.137 / Net I/σ(I): 28.39
Reflection shell
Resolution (Å)Highest resolution (Å)Rmerge(I) obsMean I/σ(I) obsDiffraction-ID% possible all
2.5-2.571.6472.761100
2.57-2.641.2493.781100
2.64-2.711.0434.591100
2.71-2.80.8585.61100
2.8-2.890.6647.461100
2.89-2.990.48610.491100
2.99-3.10.40812.71100
3.1-3.230.30217.15198.9
3.23-3.370.22722.681100
3.37-3.540.17128.91100
3.54-3.730.12836.591100
3.73-3.950.10344.871100
3.95-4.230.08454.241100
4.23-4.570.07460.121100
4.57-50.06566.691100
5-5.590.06860.661100
5.59-6.460.0760.71100
6.46-7.910.05774.511100
7.91-11.180.03999.891100
11.180.039101.65198.3

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Processing

Software
NameVersionClassification
REFMAC5.8.0135refinement
XSCALENov. 2013data scaling
PDB_EXTRACT3.2data extraction
XDSNov. 2013data reduction
PHASER2.5.1phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3vjo

3vjo


Resolution: 2.5→46.31 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.936 / SU B: 8.91 / SU ML: 0.19 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.276 / ESU R Free: 0.226
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2391 912 5 %RANDOM
Rwork0.1961 ---
obs0.1982 17313 99.98 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 200.63 Å2 / Biso mean: 60.698 Å2 / Biso min: 31.75 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refinement stepCycle: final / Resolution: 2.5→46.31 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2333 0 30 21 2384
Biso mean--53.26 50.74 -
Num. residues----291
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0170.0192417
X-RAY DIFFRACTIONr_bond_other_d0.0090.022377
X-RAY DIFFRACTIONr_angle_refined_deg1.7751.9943272
X-RAY DIFFRACTIONr_angle_other_deg2.7533.0045479
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4865288
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.09724.059101
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.92215444
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.2681515
X-RAY DIFFRACTIONr_chiral_restr0.0930.2364
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0212631
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02515
X-RAY DIFFRACTIONr_mcbond_it5.5065.7571161
X-RAY DIFFRACTIONr_mcbond_other5.4995.7541160
X-RAY DIFFRACTIONr_mcangle_it8.4968.6021446
LS refinement shellResolution: 2.501→2.566 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.384 66 -
Rwork0.336 1250 -
all-1316 -
obs--100 %

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