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- PDB-4g5j: Crystal structure of EGFR kinase in complex with BIBW2992 -

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Basic information

Entry
Database: PDB / ID: 4g5j
TitleCrystal structure of EGFR kinase in complex with BIBW2992
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / PROTEIN KINASE / 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 / morphogenesis of an epithelial fold / ERBB2 Activates PTK6 Signaling / 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 / positive regulation of DNA replication / GAB1 signalosome / positive regulation of nitric oxide mediated signal transduction / salivary gland morphogenesis / regulation of peptidyl-tyrosine phosphorylation / peptidyl-tyrosine autophosphorylation / positive regulation of phosphorylation / positive regulation of glial cell proliferation / positive regulation of vasoconstriction / Signaling by ERBB2 / cellular response to epidermal growth factor stimulus / cellular response to cadmium ion / positive regulation of DNA repair / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / GRB2 events in ERBB2 signaling / neurogenesis / transmembrane receptor protein tyrosine kinase activity / cellular response to dexamethasone stimulus / SHC1 events in ERBB2 signaling / 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 / Signal transduction by L1 / epithelial cell proliferation / cellular response to estradiol stimulus / liver regeneration / NOTCH3 Activation and Transmission of Signal to the Nucleus / positive regulation of epithelial cell proliferation / astrocyte activation / cellular response to amino acid stimulus / positive regulation of protein localization to plasma membrane / EGFR downregulation / lung development / clathrin-coated endocytic vesicle membrane / positive regulation of smooth muscle cell proliferation / Signaling by ERBB2 TMD/JMD mutants / 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 / ruffle membrane / Downregulation of ERBB2 signaling / kinase binding
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-0WM / Chem-0WN / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.8 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

Downloads & links

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Assembly

Deposited unit
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,0394
Polymers37,5791
Non-polymers1,4603
Water46826
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: Epidermal growth factor receptor
hetero molecules

A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)78,0798
Polymers75,1592
Non-polymers2,9206
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_655-x+1,-y,z1
Buried area3340 Å2
ΔGint-14 kcal/mol
Surface area29410 Å2
MethodPISA
Unit cell
Length a, b, c (Å)144.468, 144.468, 144.468
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 / / Proto-oncogene c-ErbB-1 / Receptor tyrosine-protein kinase erbB-1


Mass: 37579.457 Da / Num. of mol.: 1 / Fragment: Kinase dimain, 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: Chemical ChemComp-0WM / (2E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-7-[(3S)-tetrahydrofuran-3-yloxy]quinazolin-6-yl}-4-(dimethylamino)but-2-enamide / Afatinib / Afatinib


Mass: 485.938 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H25ClFN5O3 / Comment: medication, inhibitor*YM
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 26 / 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: 3.48 Å3/Da / Density % sol: 64.67 %

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.9999 / Wavelength: 1 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength
IDWavelength (Å)Relative weight
10.99991
211
ReflectionResolution: 2.8→45.685 Å / Num. obs: 12030 / % possible obs: 96 %

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
REFMAC5.2.0005refinement
PDB_EXTRACT3.11data extraction
XDSdata reduction
RefinementCor.coef. Fo:Fc: 0.935 / Cor.coef. Fo:Fc free: 0.909 / Highest resolution: 2.8 Å / Occupancy max: 1 / Occupancy min: 0 / SU B: 30.037 / SU ML: 0.286 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.87 / ESU R Free: 0.355 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.259 674 5.6 %RANDOM
Rwork0.2051 ---
obs0.2081 12023 96.09 %-
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 max: 79.09 Å2 / Biso mean: 62.79 Å2 / Biso min: 11.18 Å2
Refinement stepCycle: LAST / Highest resolution: 2.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2471 0 102 26 2599
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0222580
X-RAY DIFFRACTIONr_bond_other_d0.0020.022363
X-RAY DIFFRACTIONr_angle_refined_deg1.172.0153507
X-RAY DIFFRACTIONr_angle_other_deg0.76235463
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.2885306
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.78523.725102
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.12515426
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.2471515
X-RAY DIFFRACTIONr_chiral_restr0.0610.2386
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.022804
X-RAY DIFFRACTIONr_gen_planes_other0.0080.02516
X-RAY DIFFRACTIONr_nbd_refined0.2120.2520
X-RAY DIFFRACTIONr_nbd_other0.1790.22376
X-RAY DIFFRACTIONr_nbtor_refined0.1840.21249
X-RAY DIFFRACTIONr_nbtor_other0.0860.21354
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1450.263
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1050.221
X-RAY DIFFRACTIONr_symmetry_vdw_other0.1530.275
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1210.26
X-RAY DIFFRACTIONr_mcbond_it1.50221993
X-RAY DIFFRACTIONr_mcbond_other0.2452619
X-RAY DIFFRACTIONr_mcangle_it1.9532479
X-RAY DIFFRACTIONr_scbond_it2.88741326
X-RAY DIFFRACTIONr_scangle_it4.23561028
LS refinement shellResolution: 2.8→2.873 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.408 47 -
Rwork0.327 783 -
all-830 -
obs--92.12 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
14.2722.70842.44253.85640.0566.79220.3828-0.0098-0.09130.1238-0.11570.33020.6562-0.8183-0.2670.1518-0.0279-0.07460.0073-0.027-0.065753.864-6.815-29.311
21.6386-0.22550.42772.6632-0.24022.7365-0.0192-0.07090.1857-0.07-0.10420.2342-0.1534-0.14510.1233-0.0851-0.0311-0.0075-0.119-0.0697-0.109760.916.816-21.168
38.5104-1.10945.08093.0954-5.583511.2406-0.1223-1.24121.22630.2876-0.2233-0.4192-1.41730.33570.34560.2508-0.13230.11320.1786-0.11340.124684.97412.118-15.44
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A696 - 793
2X-RAY DIFFRACTION2A794 - 1000
3X-RAY DIFFRACTION3A1001 - 1016

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