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- PDB-6jz0: Crystal structure of EGFR kinase domain in complex with compound 78 -

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Basic information

Entry
Database: PDB / ID: 6jz0
TitleCrystal structure of EGFR kinase domain in complex with compound 78
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE/INHIBITOR / kinase / ATP binding site / covalent bonding with ligand / TRANSFERASE-INHIBITOR complex
Function / homology
Function and homology information


positive regulation of protein kinase C activity / multivesicular body, internal vesicle lumen / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / response to hydroxyisoflavone / diterpenoid metabolic process / Shc-EGFR complex / Inhibition of Signaling by Overexpressed EGFR / ovulation cycle / EGFR interacts with phospholipase C-gamma ...positive regulation of protein kinase C activity / multivesicular body, internal vesicle lumen / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / response to hydroxyisoflavone / diterpenoid metabolic process / Shc-EGFR complex / Inhibition of Signaling by Overexpressed EGFR / ovulation cycle / EGFR interacts with phospholipase C-gamma / positive regulation of mucus secretion / epidermal growth factor binding / regulation of peptidyl-tyrosine phosphorylation / response to UV-A / tongue development / PLCG1 events in ERBB2 signaling / midgut development / ERBB2-EGFR signaling pathway / digestive tract morphogenesis / hydrogen peroxide metabolic process / morphogenesis of an epithelial fold / PTK6 promotes HIF1A stabilization / ERBB2 Activates PTK6 Signaling / Signaling by EGFR / intracellular vesicle / response to cobalamin / negative regulation of epidermal growth factor receptor signaling pathway / eyelid development in camera-type eye / cerebral cortex cell migration / protein insertion into membrane / ERBB2 Regulates Cell Motility / protein tyrosine kinase activator activity / Signaling by ERBB4 / Respiratory syncytial virus (RSV) attachment and entry / PI3K events in ERBB2 signaling / negative regulation of mitotic cell cycle / MAP kinase kinase kinase activity / hair follicle development / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / positive regulation of G1/S transition of mitotic cell cycle / GAB1 signalosome / positive regulation of bone resorption / embryonic placenta development / positive regulation of phosphorylation / salivary gland morphogenesis / peptidyl-tyrosine autophosphorylation / positive regulation of peptidyl-serine phosphorylation / positive regulation of glial cell proliferation / positive regulation of vasoconstriction / Signaling by ERBB2 / transmembrane receptor protein tyrosine kinase activity / GRB2 events in EGFR signaling / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / GRB2 events in ERBB2 signaling / SHC1 events in ERBB2 signaling / cellular response to epidermal growth factor stimulus / cellular response to dexamethasone stimulus / positive regulation of synaptic transmission, glutamatergic / ossification / positive regulation of DNA repair / neuron projection morphogenesis / positive regulation of superoxide anion generation / positive regulation of epithelial cell proliferation / liver regeneration / epithelial cell proliferation / basal plasma membrane / Signal transduction by L1 / positive regulation of DNA replication / positive regulation of protein localization to plasma membrane / astrocyte activation / phosphatidylinositol 3-kinase/protein kinase B signal transduction / NOTCH3 Activation and Transmission of Signal to the Nucleus / cellular response to amino acid stimulus / positive regulation of smooth muscle cell proliferation / cellular response to estradiol stimulus / lung development / EGFR downregulation / synaptic membrane / Signaling by ERBB2 TMD/JMD mutants / clathrin-coated endocytic vesicle membrane / placental growth factor receptor activity / insulin receptor activity / vascular endothelial growth factor receptor activity / Constitutive Signaling by EGFRvIII / hepatocyte growth factor receptor activity / macrophage colony-stimulating factor receptor activity / platelet-derived growth factor alpha-receptor activity / platelet-derived growth factor beta-receptor activity / stem cell factor receptor activity / boss receptor activity / protein tyrosine kinase collagen receptor activity / brain-derived neurotrophic factor receptor activity / transmembrane-ephrin receptor activity / GPI-linked ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / insulin-like growth factor receptor activity / Signaling by ERBB2 ECD mutants
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 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-CKO / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.86 Å
AuthorsPeng, Y.H. / Wu, J.S. / Wu, S.Y.
CitationJournal: J.Med.Chem. / Year: 2019
Title: Discovery of a Furanopyrimidine-Based Epidermal Growth Factor Receptor Inhibitor (DBPR112) as a Clinical Candidate for the Treatment of Non-Small Cell Lung Cancer.
Authors: Lin, S.Y. / Chang Hsu, Y. / Peng, Y.H. / Ke, Y.Y. / Lin, W.H. / Sun, H.Y. / Shiao, H.Y. / Kuo, F.M. / Chen, P.Y. / Lien, T.W. / Chen, C.H. / Chu, C.Y. / Wang, S.Y. / Yeh, K.C. / Chen, C.P. / ...Authors: Lin, S.Y. / Chang Hsu, Y. / Peng, Y.H. / Ke, Y.Y. / Lin, W.H. / Sun, H.Y. / Shiao, H.Y. / Kuo, F.M. / Chen, P.Y. / Lien, T.W. / Chen, C.H. / Chu, C.Y. / Wang, S.Y. / Yeh, K.C. / Chen, C.P. / Hsu, T.A. / Wu, S.Y. / Yeh, T.K. / Chen, C.T. / Hsieh, H.P.
History
DepositionApr 30, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 4, 2019Provider: repository / Type: Initial release
Revision 1.1Nov 22, 2023Group: 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)37,7812
Polymers37,2471
Non-polymers5341
Water362
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area17250 Å2
Unit cell
Length a, b, c (Å)145.124, 145.124, 145.124
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


Mass: 37247.078 Da / Num. of mol.: 1 / Fragment: UNP residues 696-1021
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EGFR / Cell line (production host): High Five / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P00533, receptor protein-tyrosine kinase
#2: Chemical ChemComp-CKO / E-4-(dimethylamino)-N-[3-[4-[[(1S)-2-oxidanyl-1-phenyl-ethyl]amino]-6-phenyl-furo[2,3-d]pyrimidin-5-yl]phenyl]but-2-enamide


Mass: 533.620 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H31N5O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 2 / 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: 63.8 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 1.0M Ammonium citrate tribase, 0.1M Bis-Tris propane, pH7.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSRRC / Beamline: BL13C1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Dec 21, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.86→30 Å / Num. obs: 11675 / % possible obs: 97.9 % / Redundancy: 3.7 % / Rmerge(I) obs: 0.074 / Χ2: 1.062 / Net I/σ(I): 10.6
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
2.86-2.963.80.47311721.068199.8
2.96-3.083.70.38111751.045199.5
3.08-3.223.70.27811761.037199.5
3.22-3.393.80.17911701.005199.2
3.39-3.63.80.1211551.057198.4
3.6-3.883.70.08811611.001198.6
3.88-4.273.70.06611691.223197.8
4.27-4.883.80.0511671.07197
4.88-6.153.80.04211511.077196.4
6.15-303.70.02711791.043193.5

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Processing

Software
NameVersionClassification
HKL-2000data reduction
HKL-2000data scaling
PHENIX1.10.1_2155refinement
PDB_EXTRACT3.25data extraction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1M17

1m17


Resolution: 2.86→26.496 Å / SU ML: 0.3 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 25.69
RfactorNum. reflection% reflection
Rfree0.2476 559 4.79 %
Rwork0.1905 --
obs0.1932 11671 97.94 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 163.68 Å2 / Biso mean: 65.3579 Å2 / Biso min: 26.71 Å2
Refinement stepCycle: final / Resolution: 2.86→26.496 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2488 0 40 2 2530
Biso mean--61.17 47.47 -
Num. residues----311
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072585
X-RAY DIFFRACTIONf_angle_d1.0243497
X-RAY DIFFRACTIONf_chiral_restr0.049385
X-RAY DIFFRACTIONf_plane_restr0.005439
X-RAY DIFFRACTIONf_dihedral_angle_d14.41583
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 4

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.8593-3.14670.34441490.245827752924100
3.1467-3.6010.29931260.21412798292499
3.601-4.53320.23441530.17042765291898
4.5332-26.4970.20811310.17982774290595

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