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- PDB-3bel: X-ray structure of EGFR in complex with oxime inhibitor -

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Basic information

Entry
Database: PDB / ID: 3bel
TitleX-ray structure of EGFR in complex with oxime inhibitor
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / kinase domain / Alternative splicing / Anti-oncogene / ATP-binding / Cell cycle / Disease mutation / Glycoprotein / Membrane / Nucleotide-binding / Phosphoprotein / Polymorphism / Receptor / Secreted / Transmembrane / Tyrosine-protein kinase / Ubl conjugation
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 / protein tyrosine kinase activator activity / Signaling by ERBB4 / 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 / neuron projection morphogenesis / basal plasma membrane / 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 / NOTCH3 Activation and Transmission of Signal to the Nucleus / astrocyte activation / liver regeneration / positive regulation of protein localization to plasma membrane / EGFR downregulation / Signaling by ERBB2 TMD/JMD mutants / cellular response to amino acid stimulus / positive regulation of smooth muscle cell proliferation / 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 / Downregulation of ERBB2 signaling / positive regulation of miRNA transcription / 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
PHOSPHATE ION / Chem-POX / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.3 Å
AuthorsAbad, M.C. / Xu, G. / Neeper, M.P. / Struble, G.T. / Gaul, M.D. / Connolly, P.J.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2008
Title: Discovery of novel 4-amino-6-arylaminopyrimidine-5-carbaldehyde oximes as dual inhibitors of EGFR and ErbB-2 protein tyrosine kinases.
Authors: Xu, G. / Searle, L.L. / Hughes, T.V. / Beck, A.K. / Connolly, P.J. / Abad, M.C. / Neeper, M.P. / Struble, G.T. / Springer, B.A. / Emanuel, S.L. / Gruninger, R.H. / Pandey, N. / Adams, M. / ...Authors: Xu, G. / Searle, L.L. / Hughes, T.V. / Beck, A.K. / Connolly, P.J. / Abad, M.C. / Neeper, M.P. / Struble, G.T. / Springer, B.A. / Emanuel, S.L. / Gruninger, R.H. / Pandey, N. / Adams, M. / Moreno-Mazza, S. / Fuentes-Pesquera, A.R. / Middleton, S.A. / Greenberger, L.M.
History
DepositionNov 19, 2007Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 1, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 25, 2017Group: Refinement description / Category: software
Revision 1.3Aug 30, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)36,6964
Polymers36,0711
Non-polymers6253
Water48627
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)45.499, 67.686, 103.252
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Epidermal growth factor receptor / Receptor tyrosine-protein kinase ErbB-1


Mass: 36070.809 Da / Num. of mol.: 1 / Fragment: Residues 702-1016
Source method: isolated from a genetically manipulated source
Details: Expressed open reading frame of construct is MHHHHHHVDLVPRGSHMA-(EGFR1 S671-G998
Source: (gene. exp.) Homo sapiens (human) / Strain: human strains undefined / Gene: EGFR, ERBB1 / Plasmid: modified pDEST8 / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): sf9
References: UniProt: P00533, receptor protein-tyrosine kinase
#2: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: PO4
#3: Chemical ChemComp-POX / 4-amino-6-{[1-(3-fluorobenzyl)-1H-indazol-5-yl]amino}pyrimidine-5-carbaldehyde O-(2-methoxyethyl)oxime


Mass: 435.454 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H22FN7O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 27 / 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: 2.2 Å3/Da / Density % sol: 44.19 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 9
Details: 2M Na/K3PO4, 0.1M Caps pH 9.0 and 0.2M Li2SO4, VAPOR DIFFUSION, HANGING DROP, temperature 295K

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Data collection

DiffractionMean temperature: 200 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 14-ID-B / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Mar 16, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.3→50 Å / Num. obs: 14413 / % possible obs: 97.1 % / Redundancy: 4.6 % / Biso Wilson estimate: 33 Å2 / Rmerge(I) obs: 0.108 / Χ2: 1.413 / Net I/σ(I): 14.8
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
2.3-2.384.80.18714451.353100
2.38-2.484.80.17814591.466100
2.48-2.594.80.15314521.399100
2.59-2.734.80.13214551.505100
2.73-2.94.80.12314591.31199.9
2.9-3.124.80.1114641.42999.7
3.12-3.444.70.09914591.4998.6
3.44-3.934.30.114241.42995.2
3.93-4.9540.09613661.33989.9
4.95-504.10.10714301.39388.5

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
CNSrefinement
PDB_EXTRACT3data extraction
HKL-2000data collection
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: pdb id 2RGP

2rgp


Resolution: 2.3→50 Å / Isotropic thermal model: anisotropic / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.281 1455 9.9 %random
Rwork0.241 ---
obs-14321 97 %-
Displacement parametersBiso mean: 47.543 Å2
Baniso -1Baniso -2Baniso -3
1--11.488 Å20 Å20 Å2
2--5.989 Å20 Å2
3---5.499 Å2
Refinement stepCycle: LAST / Resolution: 2.3→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2250 0 42 27 2319
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_mcbond_it1.5861.5
X-RAY DIFFRACTIONc_scbond_it2.2752
X-RAY DIFFRACTIONc_mcangle_it2.7232
X-RAY DIFFRACTIONc_scangle_it3.3822.5
Xplor file
Refine-IDSerial noParam file
X-RAY DIFFRACTION1MSI_CNX_TOPPAR:protein_rep.param
X-RAY DIFFRACTION2inh.par
X-RAY DIFFRACTION3MSI_CNX_TOPPAR:water_rep.param
X-RAY DIFFRACTION4MSI_CNX_TOPPAR:ion.param

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