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- PDB-4g5p: Crystal structure of EGFR kinase T790M in complex with BIBW2992 -

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Basic information

Entry
Database: PDB / ID: 4g5p
TitleCrystal structure of EGFR kinase T790M in complex with BIBW2992
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / EGF RECEPTOR KINASE MUTANT T790M / 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 / regulation of nitric-oxide synthase activity / ERBB2 Activates PTK6 Signaling / morphogenesis of an epithelial fold / 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 / positive regulation of cyclin-dependent protein serine/threonine kinase activity / PI3K events in ERBB2 signaling / 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 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 / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / positive regulation of DNA repair / EGFR Transactivation by Gastrin / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / GRB2 events in ERBB2 signaling / transmembrane receptor protein tyrosine kinase activity / neurogenesis / SHC1 events in ERBB2 signaling / cellular response to dexamethasone stimulus / ossification / positive regulation of synaptic transmission, glutamatergic / basal plasma membrane / regulation of ERK1 and ERK2 cascade / 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 / liver regeneration / NOTCH3 Activation and Transmission of Signal to the Nucleus / astrocyte activation / cellular response to amino acid stimulus / positive regulation of protein localization to plasma membrane / EGFR downregulation / positive regulation of smooth muscle cell proliferation / lung development / Signaling by ERBB2 TMD/JMD mutants / clathrin-coated endocytic vesicle membrane / 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 / Downregulation of ERBB2 signaling / ruffle membrane / cellular response to reactive oxygen species
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-0WN / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 3.17 Å
AuthorsSolca, F. / Dahl, G. / Zoephel, A. / Bader, G. / Sanderson, M. / Klein, C. / Kraemer, O. / Himmelsbach, F. / Haaksma, E. / Adolf, G.R.
CitationJournal: J.Pharmacol.Exp.Ther. / Year: 2012
Title: Target Binding Properties and Cellular Activity of Afatinib (BIBW 2992), an Irreversible ErbB Family Blocker.
Authors: Solca, F. / Dahl, G. / Zoephel, A. / Bader, G. / Sanderson, M. / Klein, C. / Kraemer, O. / Himmelsbach, F. / Haaksma, E. / Adolf, G.R.
History
DepositionJul 18, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 29, 2012Provider: repository / Type: Initial release
Revision 1.1Oct 31, 2012Group: Database references

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Epidermal growth factor receptor
B: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,7073
Polymers75,2192
Non-polymers4881
Water68538
1
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,0982
Polymers37,6101
Non-polymers4881
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Epidermal growth factor receptor


Theoretical massNumber of molelcules
Total (without water)37,6101
Polymers37,6101
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2100 Å2
ΔGint-14 kcal/mol
Surface area28540 Å2
MethodPISA
Unit cell
Length a, b, c (Å)51.230, 89.430, 164.680
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 37609.547 Da / Num. of mol.: 2 / Fragment: Kinase domain, UNP residues 696-1022
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human)
References: UniProt: P00533, receptor protein-tyrosine kinase
#2: Chemical ChemComp-0WN / N-{4-[(3-chloro-4-fluorophenyl)amino]-7-[(3S)-tetrahydrofuran-3-yloxy]quinazolin-6-yl}-4-(dimethylamino)butanamide / Afatinib, bound form / Afatinib


Mass: 487.954 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H27ClFN5O3 / Comment: medication, inhibitor*YM
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 38 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.61 Å3/Da / Density % sol: 52.93 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.17→82.48 Å / Num. obs: 11931 / % possible obs: 89.9 % / Observed criterion σ(I): 0 / Redundancy: 4.3 % / Rsym value: 0.13 / Net I/σ(I): 4.9
Reflection shellResolution: 3.17→3.43 Å / Redundancy: 4.1 % / Rmerge(I) obs: 0.355 / Mean I/σ(I) obs: 1.8 / % possible all: 88.8

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Processing

Software
NameVersionClassification
REFMAC5.2.0005refinement
XDSdata reduction
SCALAdata scaling
RefinementResolution: 3.17→82.48 Å / Cor.coef. Fo:Fc: 0.858 / Cor.coef. Fo:Fc free: 0.733 / SU B: 35.154 / SU ML: 0.568 / Cross valid method: THROUGHOUT / ESU R Free: 0.707 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.32265 472 4 %RANDOM
Rwork0.24353 ---
obs0.24658 11432 88.63 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 43.003 Å2
Baniso -1Baniso -2Baniso -3
1-4.04 Å20 Å20 Å2
2---1.2 Å20 Å2
3----2.84 Å2
Refinement stepCycle: LAST / Resolution: 3.17→82.48 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4830 0 34 38 4902
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0224969
X-RAY DIFFRACTIONr_bond_other_d0.0010.024643
X-RAY DIFFRACTIONr_angle_refined_deg1.0651.9846719
X-RAY DIFFRACTIONr_angle_other_deg0.718310814
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.555594
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.61824.028211
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.65915915
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.6011530
X-RAY DIFFRACTIONr_chiral_restr0.0580.2750
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.025338
X-RAY DIFFRACTIONr_gen_planes_other0.0030.02955
X-RAY DIFFRACTIONr_nbd_refined0.2260.21314
X-RAY DIFFRACTIONr_nbd_other0.170.25161
X-RAY DIFFRACTIONr_nbtor_refined0.1820.22390
X-RAY DIFFRACTIONr_nbtor_other0.0810.22905
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1810.2142
X-RAY DIFFRACTIONr_xyhbond_nbd_other0.040.21
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1210.217
X-RAY DIFFRACTIONr_symmetry_vdw_other0.1780.257
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.010.22
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.43423903
X-RAY DIFFRACTIONr_mcbond_other0.18721211
X-RAY DIFFRACTIONr_mcangle_it1.79234863
X-RAY DIFFRACTIONr_scbond_it2.36342361
X-RAY DIFFRACTIONr_scangle_it3.52861856
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 3.173→3.255 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.398 28 -
Rwork0.324 748 -
obs--81.26 %

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