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- PDB-4zau: AZD9291 complex with wild type EGFR -

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Basic information

Entry
Database: PDB / ID: 4zau
TitleAZD9291 complex with wild type EGFR
ComponentsEpidermal growth factor receptor
Keywordstransferase/transferase inhibitor / transferase / kinase domain / transferase-transferase inhibitor complex
Function / homology
Function and homology information


positive regulation of protein kinase C activity / multivesicular body, internal vesicle lumen / negative regulation of cardiocyte differentiation / response to hydroxyisoflavone / diterpenoid metabolic process / positive regulation of prolactin secretion / 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 / negative regulation of cardiocyte differentiation / response to hydroxyisoflavone / diterpenoid metabolic process / positive regulation of prolactin secretion / Shc-EGFR complex / Inhibition of Signaling by Overexpressed EGFR / ovulation cycle / EGFR interacts with phospholipase C-gamma / positive regulation of mucus secretion / regulation of peptidyl-tyrosine phosphorylation / epidermal growth factor binding / tongue development / response to UV-A / PLCG1 events in ERBB2 signaling / midgut development / ERBB2-EGFR signaling pathway / hydrogen peroxide metabolic process / morphogenesis of an epithelial fold / PTK6 promotes HIF1A stabilization / ERBB2 Activates PTK6 Signaling / digestive tract morphogenesis / Signaling by EGFR / response to cobalamin / intracellular vesicle / 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 / hepatocyte growth factor receptor activity / platelet-derived growth factor beta-receptor activity / placental growth factor receptor activity / brain-derived neurotrophic factor receptor activity / boss receptor activity / platelet-derived growth factor alpha-receptor activity / epidermal growth factor receptor activity / protein tyrosine kinase activator activity / Respiratory syncytial virus (RSV) attachment and entry / macrophage colony-stimulating factor receptor activity / positive regulation of bone resorption / protein tyrosine kinase collagen receptor activity / stem cell factor receptor activity / Signaling by ERBB4 / PI3K events in ERBB2 signaling / negative regulation of mitotic cell cycle / insulin-like growth factor receptor activity / transmembrane-ephrin receptor activity / positive regulation of phosphorylation / positive regulation of peptidyl-serine phosphorylation / GPI-linked ephrin receptor activity / vascular endothelial growth factor receptor activity / peptidyl-tyrosine autophosphorylation / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / hair follicle development / MAP kinase kinase kinase activity / positive regulation of G1/S transition of mitotic cell cycle / GAB1 signalosome / embryonic placenta development / fibroblast growth factor receptor activity / insulin receptor activity / salivary gland morphogenesis / positive regulation of vasoconstriction / Signaling by ERBB2 / positive regulation of glial cell proliferation / GRB2 events in EGFR signaling / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / SHC1 events in EGFR signaling / transmembrane receptor protein tyrosine kinase activity / EGFR Transactivation by Gastrin / cellular response to dexamethasone stimulus / GRB2 events in ERBB2 signaling / positive regulation of synaptic transmission, glutamatergic / SHC1 events in ERBB2 signaling / ossification / basal plasma membrane / positive regulation of DNA repair / cellular response to epidermal growth factor stimulus / positive regulation of epithelial cell proliferation / positive regulation of superoxide anion generation / positive regulation of DNA replication / epithelial cell proliferation / neuron projection morphogenesis / Signal transduction by L1 / positive regulation of smooth muscle cell proliferation / positive regulation of protein localization to plasma membrane / liver regeneration / astrocyte activation / cellular response to amino acid stimulus / NOTCH3 Activation and Transmission of Signal to the Nucleus / cellular response to estradiol stimulus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / lung development / EGFR downregulation / synaptic membrane / peptidyl-tyrosine phosphorylation / clathrin-coated endocytic vesicle membrane / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII
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-YY3 / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsSquire, C.J. / Yosaatmadja, Y. / Flanagan, J.U. / McKeage, M.
CitationJournal: J.Struct.Biol. / Year: 2015
Title: Binding mode of the breakthrough inhibitor AZD9291 to epidermal growth factor receptor revealed.
Authors: Yosaatmadja, Y. / Silva, S. / Dickson, J.M. / Patterson, A.V. / Smaill, J.B. / Flanagan, J.U. / McKeage, M.J. / Squire, C.J.
History
DepositionApr 14, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 11, 2015Provider: repository / Type: Initial release
Revision 1.1Nov 18, 2015Group: Database references
Revision 1.2Dec 2, 2015Group: Database references
Revision 1.3Sep 9, 2020Group: Database references / Derived calculations / Structure summary
Category: chem_comp / citation / pdbx_struct_oper_list
Item: _chem_comp.pdbx_synonyms / _citation.journal_id_CSD / _pdbx_struct_oper_list.symmetry_operation
Revision 1.4Sep 27, 2023Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)38,0632
Polymers37,5631
Non-polymers5001
Water724
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)144.886, 144.886, 144.886
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: 37563.457 Da / Num. of mol.: 1 / Fragment: unp residues 696-1022
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EGFR, ERBB, ERBB1, HER1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P00533, receptor protein-tyrosine kinase
#2: Chemical ChemComp-YY3 / N-(2-{[2-(dimethylamino)ethyl](methyl)amino}-4-methoxy-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide / Osimertinib / AZD 9291


Mass: 499.607 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H33N7O2 / Comment: medication, inhibitor*YM
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 4 / 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: 3.37 Å3/Da / Density % sol: 63.54 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7 / Details: 0.1 M MES, 1 M sodium citrate

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.5418 Å
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE / Date: Nov 17, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.8→19.36 Å / Num. obs: 12574 / % possible obs: 99.7 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 38.1 % / Net I/σ(I): 20.9
Reflection shellResolution: 2.8→2.95 Å / Redundancy: 38 % / Mean I/σ(I) obs: 2.3 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.8.0073refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4WRG

4wrg


Resolution: 2.8→19.36 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.92 / SU B: 28.155 / SU ML: 0.248 / Cross valid method: THROUGHOUT / ESU R: 0.469 / ESU R Free: 0.3 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24411 628 5 %RANDOM
Rwork0.19344 ---
obs0.19604 11944 99.59 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 59.318 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refinement stepCycle: 1 / Resolution: 2.8→19.36 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2177 0 37 4 2218
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0192263
X-RAY DIFFRACTIONr_bond_other_d0.0030.022152
X-RAY DIFFRACTIONr_angle_refined_deg1.5781.9843080
X-RAY DIFFRACTIONr_angle_other_deg1.4963.0044924
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3585278
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.31324.0786
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.315365
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.9081510
X-RAY DIFFRACTIONr_chiral_restr0.0810.2355
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0212496
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02488
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_it2.4174.1871127
X-RAY DIFFRACTIONr_mcbond_other2.414.1871126
X-RAY DIFFRACTIONr_mcangle_it3.8226.281401
X-RAY DIFFRACTIONr_mcangle_other3.8136.2771401
X-RAY DIFFRACTIONr_scbond_it2.8064.4231136
X-RAY DIFFRACTIONr_scbond_other2.8044.4251137
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.4286.5291680
X-RAY DIFFRACTIONr_long_range_B_refined5.9434.0042532
X-RAY DIFFRACTIONr_long_range_B_other5.93934.0172533
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.801→2.873 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.378 63 -
Rwork0.299 852 -
obs--100 %
Refinement TLS params.Method: refined / Origin x: -9.0604 Å / Origin y: -58.7914 Å / Origin z: 24.4455 Å
111213212223313233
T0.1308 Å20.0403 Å2-0.0485 Å2-0.0363 Å2-0.0453 Å2--0.0736 Å2
L4.4992 °21.4391 °21.4903 °2-1.1722 °20.9273 °2--2.0344 °2
S-0.1559 Å °-0.3463 Å °0.4332 Å °-0.1255 Å °-0.0876 Å °0.0481 Å °-0.4677 Å °-0.1868 Å °0.2435 Å °

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