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- PDB-4jq7: Crystal structure of EGFR kinase domain in complex with compound 2a -

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Basic information

Entry
Database: PDB / ID: 4jq7
TitleCrystal structure of EGFR kinase domain in complex with compound 2a
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Transferase / tyrosine kinase domain / ATP-binding domain / autophosphorylation / TRANSFERASE-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 / response to UV-A / tongue development / PLCG1 events in ERBB2 signaling / midgut development / ERBB2-EGFR signaling pathway / digestive tract morphogenesis / PTK6 promotes HIF1A stabilization / hydrogen peroxide metabolic process / morphogenesis of an epithelial fold / 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 / Signaling by ERBB4 / cerebral cortex cell migration / ERBB2 Regulates Cell Motility / protein insertion into membrane / protein tyrosine kinase activator activity / 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 / positive regulation of G1/S transition of mitotic cell cycle / embryonic placenta development / GAB1 signalosome / positive regulation of bone resorption / regulation of peptidyl-tyrosine phosphorylation / positive regulation of phosphorylation / salivary gland morphogenesis / peptidyl-tyrosine autophosphorylation / 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 / cellular response to epidermal growth factor stimulus / SHC1 events in ERBB2 signaling / positive regulation of DNA repair / cellular response to dexamethasone stimulus / positive regulation of synaptic transmission, glutamatergic / ossification / neuron projection morphogenesis / positive regulation of epithelial cell proliferation / basal plasma membrane / positive regulation of superoxide anion generation / liver regeneration / epithelial cell proliferation / Signal transduction by L1 / positive regulation of DNA replication / neurogenesis / positive regulation of protein localization to plasma membrane / astrocyte activation / NOTCH3 Activation and Transmission of Signal to the Nucleus / positive regulation of smooth muscle cell proliferation / cellular response to amino acid stimulus / lung development / cellular response to estradiol stimulus / EGFR downregulation / clathrin-coated endocytic vesicle membrane / synaptic membrane / epidermal growth factor receptor signaling pathway / Signaling by ERBB2 TMD/JMD mutants / 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 / GPI-linked ephrin receptor activity / transmembrane-ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / positive regulation of peptidyl-serine phosphorylation
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-KJQ / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.73 Å
AuthorsPeng, Y.H. / Wu, J.S.
CitationJournal: J.Med.Chem. / Year: 2013
Title: Protein Kinase Inhibitor Design by Targeting the Asp-Phe-Gly (DFG) Motif: The Role of the DFG Motif in the Design of Epidermal Growth Factor Receptor Inhibitors
Authors: Peng, Y.H. / Shiao, H.Y. / Tu, C.H. / Liu, P.M. / Hsu, J.T. / Amancha, P.K. / Wu, J.S. / Coumar, M.S. / Chen, C.H. / Wang, S.Y. / Lin, W.H. / Sun, H.Y. / Chao, Y.S. / Lyu, P.C. / Hsieh, H.P. / Wu, S.Y.
History
DepositionMar 20, 2013Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Jun 19, 2013Provider: repository / Type: Initial release
Revision 1.1Nov 8, 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_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _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)37,8092
Polymers37,4011
Non-polymers4071
Water45025
1
A: Epidermal growth factor receptor
hetero molecules

A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,6174
Polymers74,8032
Non-polymers8152
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555x,-y,-z1
Buried area1990 Å2
ΔGint-6 kcal/mol
Surface area30410 Å2
MethodPISA
Unit cell
Length a, b, c (Å)145.933, 145.933, 145.933
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 / Proto-oncogene c-ErbB-1 / Receptor tyrosine-protein kinase erbB-1


Mass: 37401.250 Da / Num. of mol.: 1 / Fragment: tyrosine kinase domain, UNP residues 696-1021
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EGFR / Plasmid: pBacPAK-MT-EGFP / Cell line (production host): Hi5 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P00533, receptor protein-tyrosine kinase
#2: Chemical ChemComp-KJQ / (2S)-2-[(5,6-diphenylfuro[2,3-d]pyrimidin-4-yl)amino]-2-phenylethanol


Mass: 407.464 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H21N3O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 25 / 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: 3.46 Å3/Da / Density % sol: 64.47 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 1.0M Ammonium citrate tribase, 0.1M Bis-Tris propane, pH 7.0, VAPOR DIFFUSION, HANGING DROP, temperature 291K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL12B2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: May 25, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.73→30 Å / Num. all: 13929 / Num. obs: 13929 / % possible obs: 99.1 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 7.49 % / Rmerge(I) obs: 0.081 / Net I/σ(I): 15.52
Reflection shellResolution: 2.73→2.83 Å / Redundancy: 3.5 % / Rmerge(I) obs: 0.498 / Mean I/σ(I) obs: 2.56 / Num. unique all: 1364 / % possible all: 98.6

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Processing

Software
NameVersionClassification
HKL-2000data collection
MOLREP9.2phasing
REFMAC5.6.0117refinement
HKL-2000data reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 1M17

1m17


Resolution: 2.73→30 Å / Cor.coef. Fo:Fc: 0.935 / Cor.coef. Fo:Fc free: 0.908 / SU B: 23.871 / SU ML: 0.223 / Cross valid method: THROUGHOUT / ESU R: 0.504 / ESU R Free: 0.287 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23714 691 5 %RANDOM
Rwork0.2068 ---
obs0.20835 13086 99.02 %-
all-13929 --
Solvent computationIon probe radii: 0.9 Å / Shrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: MASK
Displacement parametersBiso mean: 53.184 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refinement stepCycle: LAST / Resolution: 2.73→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2409 0 31 25 2465
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.022496
X-RAY DIFFRACTIONr_bond_other_d0.0020.021716
X-RAY DIFFRACTIONr_angle_refined_deg0.9451.9923380
X-RAY DIFFRACTIONr_angle_other_deg0.8193.0034193
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.9615301
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.71824.286105
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.93615449
X-RAY DIFFRACTIONr_dihedral_angle_4_deg11.861514
X-RAY DIFFRACTIONr_chiral_restr0.0530.2374
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.0212712
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02491
LS refinement shellResolution: 2.73→2.801 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.424 36 -
Rwork0.346 912 -
obs--98.44 %
Refinement TLS params.Method: refined / Origin x: -58.636 Å / Origin y: -9.896 Å / Origin z: -23.942 Å
111213212223313233
T0.0577 Å2-0.0055 Å20.0551 Å2-0.0996 Å20.042 Å2--0.0853 Å2
L0.9594 °20.1233 °2-0.5427 °2-2.0662 °2-0.6769 °2--2.1923 °2
S-0.0961 Å °-0.0432 Å °-0.0524 Å °-0.2681 Å °-0.1344 Å °-0.407 Å °0.082 Å °0.4138 Å °0.2304 Å °

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