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- PDB-2j6m: Crystal structure of EGFR kinase domain in complex with AEE788 -

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Basic information

Entry
Database: PDB / ID: 2j6m
TitleCrystal structure of EGFR kinase domain in complex with AEE788
ComponentsEPIDERMAL GROWTH FACTOR RECEPTOR
KeywordsTRANSFERASE / CELL CYCLE / ATP-BINDING / POLYMORPHISM / NUCLEOTIDE-BINDING / ALTERNATIVE SPLICING / TYROSINE-PROTEIN KINASE / EPIDERMAL GROWTH FACTOR / UBL CONJUGATION / PHOSPHORYLATION / DISEASE MUTATION / GLYCOPROTEIN / ANTI-ONCOGENE / TRANSMEMBRANE / EGFR / KINASE / AEE788 / MEMBRANE / RECEPTOR / WILD-TYPE
Function / homology
Function and homology information


response to hydroxyisoflavone / multivesicular body, internal vesicle lumen / positive regulation of protein kinase C activity / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / 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 protein kinase C activity / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / 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 / epidermal growth factor binding / response to UV-A / tongue development / PLCG1 events in ERBB2 signaling / midgut development / hydrogen peroxide metabolic process / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / ERBB2-EGFR signaling pathway / PTK6 promotes HIF1A stabilization / digestive tract morphogenesis / morphogenesis of an epithelial fold / ERBB2 Activates PTK6 Signaling / intracellular vesicle / Signaling by EGFR / transmembrane receptor protein tyrosine kinase activator activity / negative regulation of epidermal growth factor receptor signaling pathway / response to cobalamin / Signaling by ERBB4 / protein tyrosine kinase activator activity / eyelid development in camera-type eye / protein insertion into membrane / cerebral cortex cell migration / ERBB2 Regulates Cell Motility / regulation of JNK cascade / Respiratory syncytial virus (RSV) attachment and entry / PI3K events in ERBB2 signaling / positive regulation of cyclin-dependent protein serine/threonine kinase activity / negative regulation of mitotic cell cycle / MAP kinase kinase kinase activity / hair follicle development / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / embryonic placenta development / positive regulation of bone resorption / GAB1 signalosome / positive regulation of G1/S transition of mitotic cell cycle / salivary gland morphogenesis / peptidyl-tyrosine autophosphorylation / positive regulation of phosphorylation / regulation of peptidyl-tyrosine phosphorylation / positive regulation of glial cell proliferation / Signaling by ERBB2 / positive regulation of vasoconstriction / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / cellular response to epidermal growth factor stimulus / cellular response to cadmium ion / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / GRB2 events in ERBB2 signaling / transmembrane receptor protein tyrosine kinase activity / positive regulation of DNA repair / SHC1 events in ERBB2 signaling / cellular response to dexamethasone stimulus / ossification / regulation of ERK1 and ERK2 cascade / positive regulation of synaptic transmission, glutamatergic / basal plasma membrane / neuron projection morphogenesis / neurogenesis / positive regulation of epithelial cell proliferation / positive regulation of superoxide anion generation / positive regulation of DNA replication / epithelial cell proliferation / Signal transduction by L1 / cellular response to estradiol stimulus / astrocyte activation / NOTCH3 Activation and Transmission of Signal to the Nucleus / liver regeneration / positive regulation of protein localization to plasma membrane / Signaling by ERBB2 TMD/JMD mutants / cellular response to amino acid stimulus / positive regulation of smooth muscle cell proliferation / EGFR downregulation / lung development / positive regulation of MAP kinase activity / Constitutive Signaling by EGFRvIII / clathrin-coated endocytic vesicle membrane / Signaling by ERBB2 ECD mutants / epidermal growth factor receptor signaling pathway / Signaling by ERBB2 KD Mutants / negative regulation of protein catabolic process / receptor protein-tyrosine kinase / kinase binding / positive regulation of miRNA transcription / Downregulation of ERBB2 signaling / cell-cell adhesion / ruffle membrane / HCMV Early Events
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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / 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-AEE / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.1 Å
AuthorsYun, C.-H. / Boggon, T.J. / Li, Y. / Woo, S. / Greulich, H. / Meyerson, M. / Eck, M.J.
CitationJournal: Cancer Cell / Year: 2007
Title: Structures of Lung Cancer-Derived Egfr Mutants and Inhibitor Complexes: Mechanism of Activation and Insights Into Differential Inhibitor Sensitivity
Authors: Yun, C.-H. / Boggon, T.J. / Li, Y. / Woo, S. / Greulich, H. / Meyerson, M. / Eck, M.J.
History
DepositionSep 29, 2006Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 3, 2007Provider: repository / Type: Initial release
Revision 1.1Jun 2, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Dec 13, 2023Group: Data collection / Database references ...Data collection / Database references / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf

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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)37,7452
Polymers37,3041
Non-polymers4411
Water1,18966
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)145.309, 145.309, 145.309
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number197
Space group name H-MI23

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Components

#1: Protein EPIDERMAL GROWTH FACTOR RECEPTOR / RECEPTOR TYROSINE-PROTEIN KINASE ERBB-1


Mass: 37304.129 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN, RESIDUES 696-1022
Source method: isolated from a genetically manipulated source
Details: EGFR 696-1022 WILD-TYPE / Source: (gene. exp.) HOMO SAPIENS (human) / Description: EGFR 696-1022 WILD-TYPE / Plasmid: PACG2T / Cell line (production host): SF9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: P00533, EC: 2.7.1.112, receptor protein-tyrosine kinase
#2: Chemical ChemComp-AEE / 6-{4-[(4-ETHYLPIPERAZIN-1-YL)METHYL]PHENYL}-N-[(1R)-1-PHENYLETHYL]-7H-PYRROLO[2,3-D]PYRIMIDIN-4-AMINE


Mass: 440.583 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H32N6 / Comment: inhibitor*YM
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 66 / 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: 3.4 Å3/Da / Density % sol: 64 %
Crystal growpH: 7.5 / Details: 1.2M NAK TARTRATE, 0.1M HEPES 7.5, pH 7.50

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-C / Wavelength: 0.97935
DetectorType: ADSC CCD / Detector: CCD / Date: Aug 21, 2006 / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97935 Å / Relative weight: 1
ReflectionResolution: 3.1→50 Å / Num. obs: 9135 / % possible obs: 96.7 % / Observed criterion σ(I): -3 / Redundancy: 6.4 % / Rmerge(I) obs: 0.07 / Net I/σ(I): 22.5
Reflection shellResolution: 3.1→3.34 Å / Redundancy: 3.2 % / Rmerge(I) obs: 0.38 / Mean I/σ(I) obs: 3 / % possible all: 83.8

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1M17

1m17


Resolution: 3.1→25 Å / Cor.coef. Fo:Fc: 0.933 / Cor.coef. Fo:Fc free: 0.882 / Cross valid method: THROUGHOUT / ESU R Free: 0.431 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.249 467 5.1 %RANDOM
Rwork0.199 ---
obs0.202 8636 96.7 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 52.91 Å2
Refinement stepCycle: LAST / Resolution: 3.1→25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2433 0 33 66 2532
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0222522
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.571.993417
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg2.3675304
X-RAY DIFFRACTIONr_dihedral_angle_2_deg41.48524.393107
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.77315452
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.6531514
X-RAY DIFFRACTIONr_chiral_restr0.1210.2381
X-RAY DIFFRACTIONr_gen_planes_refined0.010.021867
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.3080.21271
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3450.21752
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2420.2105
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2860.238
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.4310.22
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.7291.51526
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it5.08722473
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.193996
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it5.0674.5944
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded

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