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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


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 / hydrogen peroxide metabolic process / PTK6 promotes HIF1A stabilization / 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 / cerebral cortex cell migration / protein insertion into membrane / ERBB2 Regulates Cell Motility / positive regulation of cyclin-dependent protein serine/threonine kinase activity / Signaling by ERBB4 / protein tyrosine kinase activator activity / Respiratory syncytial virus (RSV) attachment and entry / regulation of peptidyl-tyrosine phosphorylation / 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 / embryonic placenta development / positive regulation of bone resorption / 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 / histone H3Y41 kinase activity / histone H2AXY142 kinase activity / 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 / cellular response to dexamethasone stimulus / positive regulation of synaptic transmission, glutamatergic / ossification / positive regulation of DNA repair / positive regulation of peptidyl-serine phosphorylation / neuron projection morphogenesis / positive regulation of superoxide anion generation / positive regulation of epithelial cell proliferation / basal plasma membrane / liver regeneration / epithelial cell proliferation / Signal transduction by L1 / neurogenesis / positive regulation of DNA replication / positive regulation of protein localization to plasma membrane / astrocyte activation / 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 / cell surface receptor protein tyrosine kinase signaling pathway / 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
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
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


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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