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- PDB-2itw: Crystal structure of EGFR kinase domain in complex with AFN941 -

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Basic information

Entry
Database: PDB / ID: 2itw
TitleCrystal structure of EGFR kinase domain in complex with AFN941
ComponentsEPIDERMAL GROWTH FACTOR RECEPTOR
KeywordsTRANSFERASE / RECEPTOR / CELL CYCLE / ATP-BINDING / TRANSMEMBRANE / PHOSPHORYLATION / DISEASE MUTATION / POLYMORPHISM / GLYCOPROTEIN / ANTI-ONCOGENE / NUCLEOTIDE-BINDING / ALTERNATIVE SPLICING / AFN941 / EGFR / KINASE / STAUROSPORINE / MEMBRANE / TYROSINE-PROTEIN KINASE / EPIDERMAL GROWTH FACTOR
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 / PI3K events in ERBB2 signaling / positive regulation of cyclin-dependent protein serine/threonine kinase activity / 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 DNA replication / positive regulation of bone resorption / GAB1 signalosome / positive regulation of nitric oxide mediated signal transduction / salivary gland morphogenesis / regulation of peptidyl-tyrosine phosphorylation / peptidyl-tyrosine autophosphorylation / positive regulation of vasoconstriction / positive regulation of glial cell proliferation / positive regulation of phosphorylation / 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 / ossification / cellular response to dexamethasone stimulus / SHC1 events in ERBB2 signaling / 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 / clathrin-coated endocytic vesicle membrane / lung development / 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
1,2,3,4-Tetrahydrogen Staurosporine / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.88 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
DepositionMay 25, 2006Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 3, 2007Provider: repository / Type: Initial release
Revision 1.1Mar 27, 2013Group: Atomic model / Derived calculations ...Atomic model / Derived calculations / Non-polymer description / Other / Version format compliance
Revision 1.2Dec 13, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / 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 / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Remark 700 SHEET THE SHEET STRUCTURE OF THIS MOLECULE IS BIFURCATED. IN ORDER TO REPRESENT THIS FEATURE IN ... SHEET THE SHEET STRUCTURE OF THIS MOLECULE IS BIFURCATED. IN ORDER TO REPRESENT THIS FEATURE IN THE SHEET RECORDS BELOW, TWO SHEETS ARE DEFINED.

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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)37,7732
Polymers37,3041
Non-polymers4691
Water1,29772
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)144.446, 144.446, 144.446
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number197
Space group name H-MI23
Components on special symmetry positions
IDModelComponents
11A-3013-

HOH

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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
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PACG2T / Cell line (production host): SF9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: P00533, receptor protein-tyrosine kinase
#2: Chemical ChemComp-ITQ / 1,2,3,4-Tetrahydrogen Staurosporine / Staurosporine Analogue - AFN941


Mass: 468.547 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H28N4O3
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 72 / Source method: isolated from a natural source / Formula: H2O
Compound detailsRECEPTOR FOR EGF, BUT ALSO FOR OTHER MEMBERS OF THE EGF FAMILY, AS TGF-ALPHA, AMPHIREGULIN, ...RECEPTOR FOR EGF, BUT ALSO FOR OTHER MEMBERS OF THE EGF FAMILY, AS TGF-ALPHA, AMPHIREGULIN, BETACELLULIN, HEPARIN-BINDING EGF-LIKE GROWTH FACTOR, GP30 AND VACCINIA VIRUS GROWTH FACTOR. IS INVOLVED IN THE CONTROL OF CELL GROWTH AND DIFFERENTIATION.

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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 KNA TARTRATE, 0.1M HEPES 7.5, pH 7.50

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X25 / Wavelength: 1.1
DetectorType: ADSC QUANTUM-4 / Detector: CCD / Date: Aug 4, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1 Å / Relative weight: 1
ReflectionResolution: 2.88→50 Å / Num. obs: 11527 / % possible obs: 100 % / Observed criterion σ(I): -3 / Redundancy: 7.1 % / Rmerge(I) obs: 0.07 / Net I/σ(I): 33.6
Reflection shellResolution: 2.88→3.1 Å / Redundancy: 7.2 % / Rmerge(I) obs: 0.4 / Mean I/σ(I) obs: 5.4 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1M14

1m14


Resolution: 2.88→24.08 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.905 / Cross valid method: THROUGHOUT / ESU R: 0.934 / ESU R Free: 0.36 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.256 544 4.7 %RANDOM
Rwork0.187 ---
obs0.191 10912 99.7 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 54.1 Å2
Refinement stepCycle: LAST / Resolution: 2.88→24.08 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2395 0 35 72 2502
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0170.0222497
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.8181.9993391
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1755300
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.14424.095105
X-RAY DIFFRACTIONr_dihedral_angle_3_deg20.7515455
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.3281515
X-RAY DIFFRACTIONr_chiral_restr0.1090.2375
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.021845
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2620.21215
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3310.21704
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1870.2112
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1920.246
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2010.24
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.0061.51498
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.92522430
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.1773999
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it3.7454.5960
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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