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- PDB-4wkq: 1.85 angstrom structure of EGFR kinase domain with gefitinib -

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Entry
Database: PDB / ID: 4wkq
Title1.85 angstrom structure of EGFR kinase domain with gefitinib
ComponentsEpidermal growth factor receptor
Keywordstransferase/transferase inhibitor / inhibitor / complex / kinase / epidermal growth factor receptor / TRANSFERASE / transferase-transferase inhibitor complex
Function / homology
Function and homology information


multivesicular body, internal vesicle lumen / negative regulation of cardiocyte differentiation / Shc-EGFR complex / positive regulation of protein kinase C signaling / Inhibition of Signaling by Overexpressed EGFR / EGFR interacts with phospholipase C-gamma / epidermal growth factor receptor activity / epidermal growth factor binding / response to UV-A / regulation of peptidyl-tyrosine phosphorylation ...multivesicular body, internal vesicle lumen / negative regulation of cardiocyte differentiation / Shc-EGFR complex / positive regulation of protein kinase C signaling / Inhibition of Signaling by Overexpressed EGFR / EGFR interacts with phospholipase C-gamma / epidermal growth factor receptor activity / epidermal growth factor binding / response to UV-A / regulation of peptidyl-tyrosine phosphorylation / PLCG1 events in ERBB2 signaling / ERBB2-EGFR signaling pathway / PTK6 promotes HIF1A stabilization / ERBB2 Activates PTK6 Signaling / Signaling by EGFR / intracellular vesicle / negative regulation of epidermal growth factor receptor signaling pathway / ERBB2 Regulates Cell Motility / Developmental Lineage of Mammary Gland Myoepithelial Cells / protein insertion into membrane / Signaling by ERBB4 / Respiratory syncytial virus (RSV) attachment and entry / PI3K events in ERBB2 signaling / positive regulation of phosphorylation / positive regulation of peptidyl-serine phosphorylation / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / MAP kinase kinase kinase activity / GAB1 signalosome / protein tyrosine kinase activator activity / ossification / positive regulation of G1/S transition of mitotic cell cycle / Signaling by ERBB2 / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / transmembrane receptor protein tyrosine kinase activity / positive regulation of epithelial cell proliferation / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / GRB2 events in ERBB2 signaling / cellular response to amino acid stimulus / SHC1 events in ERBB2 signaling / positive regulation of fibroblast proliferation / cellular response to epidermal growth factor stimulus / basal plasma membrane / positive regulation of DNA replication / positive regulation of DNA repair / phosphatidylinositol 3-kinase/protein kinase B signal transduction / Signal transduction by L1 / cellular response to estradiol stimulus / positive regulation of protein localization to plasma membrane / negative regulation of protein catabolic process / clathrin-coated endocytic vesicle membrane / NOTCH3 Activation and Transmission of Signal to the Nucleus / cell-cell adhesion / Signaling by ERBB2 TMD/JMD mutants / EGFR downregulation / Constitutive Signaling by EGFRvIII / receptor protein-tyrosine kinase / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / positive regulation of miRNA transcription / positive regulation of protein phosphorylation / cell junction / epidermal growth factor receptor signaling pathway / kinase binding / ruffle membrane / Downregulation of ERBB2 signaling / Constitutive Signaling by Aberrant PI3K in Cancer / HCMV Early Events / positive regulation of canonical Wnt signaling pathway / actin filament binding / PIP3 activates AKT signaling / neuron differentiation / transmembrane signaling receptor activity / positive regulation of cell growth / Cargo recognition for clathrin-mediated endocytosis / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / Clathrin-mediated endocytosis / nuclear membrane / ATPase binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / virus receptor activity / RAF/MAP kinase cascade / protein tyrosine kinase activity / double-stranded DNA binding / early endosome membrane / protein phosphatase binding / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / basolateral plasma membrane / positive regulation of MAPK cascade / learning or memory / positive regulation of ERK1 and ERK2 cascade / signaling receptor complex / cell surface receptor signaling pathway / Extra-nuclear estrogen signaling / endosome / endosome membrane / positive regulation of cell migration / cadherin binding / membrane raft
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 / 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
Gefitinib / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.85 Å
AuthorsYosaatmadja, Y. / Squire, C.J.
CitationJournal: To Be Published
Title: 1.85 angstrom structure of EGFR kinase domain with gefitinib
Authors: Yosaatmadja, Y. / Squire, C.J. / McKeage, M. / Flanagan, J.U.
History
DepositionOct 3, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 5, 2014Provider: repository / Type: Initial release
Revision 1.1Feb 4, 2015Group: Derived calculations
Revision 1.2Sep 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description / Source and taxonomy
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / diffrn_source / entity_src_gen / pdbx_database_related / pdbx_database_status / pdbx_initial_refinement_model / pdbx_prerelease_seq / pdbx_struct_conn_angle / pdbx_struct_oper_list / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _diffrn_source.pdbx_synchrotron_site / _entity_src_gen.pdbx_alt_source_flag / _pdbx_database_related.content_type / _pdbx_database_status.pdb_format_compatible / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_symmetry / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_symmetry / _pdbx_struct_conn_angle.value / _pdbx_struct_oper_list.symmetry_operation / _struct_conn.pdbx_dist_value / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_symmetry
Revision 1.3Mar 27, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond
Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_1 ..._chem_comp_atom.atom_id / _chem_comp_bond.atom_id_1 / _chem_comp_bond.atom_id_2 / _chem_comp_bond.pdbx_aromatic_flag / _chem_comp_bond.pdbx_stereo_config / _chem_comp_bond.value_order

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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)38,2454
Polymers37,5791
Non-polymers6653
Water2,180121
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)143.714, 143.714, 143.714
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-1241-

HOH

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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: unp residues 696-1022
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line: Sf9 / Gene: EGFR, ERBB, ERBB1, HER1 / Plasmid: pFASTBacHTb / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P00533, receptor protein-tyrosine kinase
#2: Chemical ChemComp-IRE / Gefitinib


Mass: 446.902 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H24ClFN4O3 / Comment: medication, inhibitor*YM
#3: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#4: Chemical ChemComp-MES / 2-(N-MORPHOLINO)-ETHANESULFONIC ACID


Mass: 195.237 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H13NO4S / Comment: pH buffer*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 121 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 3.29 Å3/Da / Density % sol: 62.63 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7 / Details: 0.1 M MES, pH 7.0, 1 M sodium citrate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX1 / Wavelength: 0.9537 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Sep 16, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9537 Å / Relative weight: 1
ReflectionResolution: 1.85→101.62 Å / Num. obs: 42074 / % possible obs: 99.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 40.6 % / Net I/σ(I): 19.4
Reflection shellResolution: 1.85→1.89 Å / Redundancy: 20.3 % / Mean I/σ(I) obs: 1 / % possible all: 99.9

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Processing

SoftwareName: REFMAC / Version: 5.8.0071 / Classification: refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2ITY

2ity


Resolution: 1.85→100 Å / Cor.coef. Fo:Fc: 0.967 / Cor.coef. Fo:Fc free: 0.959 / SU B: 6.519 / SU ML: 0.095 / Cross valid method: THROUGHOUT / ESU R: 0.106 / ESU R Free: 0.106 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22457 1997 4.8 %RANDOM
Rwork0.19424 ---
obs0.19572 40025 99.8 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 43.059 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refinement stepCycle: 1 / Resolution: 1.85→100 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2317 0 44 121 2482
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0192441
X-RAY DIFFRACTIONr_bond_other_d0.0020.022357
X-RAY DIFFRACTIONr_angle_refined_deg1.6851.9953317
X-RAY DIFFRACTIONr_angle_other_deg1.043.0065426
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1755301
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.13224.0499
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.54515417
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.9891514
X-RAY DIFFRACTIONr_chiral_restr0.0950.2373
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0212680
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02520
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.2082.7831192
X-RAY DIFFRACTIONr_mcbond_other2.1982.7791191
X-RAY DIFFRACTIONr_mcangle_it3.3534.1421485
X-RAY DIFFRACTIONr_mcangle_other3.3524.1471486
X-RAY DIFFRACTIONr_scbond_it2.9053.1211249
X-RAY DIFFRACTIONr_scbond_other2.9053.1211249
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.4654.5531829
X-RAY DIFFRACTIONr_long_range_B_refined6.32422.9412821
X-RAY DIFFRACTIONr_long_range_B_other6.32522.9242820
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.85→1.898 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.384 137 -
Rwork0.359 2933 -
obs--99.8 %
Refinement TLS params.Method: refined / Details: chain A / Origin x: 9.394 Å / Origin y: 202.182 Å / Origin z: 23.866 Å
111213212223313233
T0.0873 Å2-0.0075 Å20.0272 Å2-0.0158 Å20.0004 Å2--0.0242 Å2
L2.8111 °20.2362 °2-1.055 °2-0.919 °2-0.2241 °2--2.3724 °2
S-0.1264 Å °-0.047 Å °-0.2248 Å °-0.015 Å °-0.0207 Å °0.0288 Å °0.3623 Å °-0.1177 Å °0.1471 Å °

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