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- PDB-9by6: Crystal structure of the kinase domain of EGFR soaked with non-co... -

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Basic information

Entry
Database: PDB / ID: 9by6
TitleCrystal structure of the kinase domain of EGFR soaked with non-covalent osimertinib
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / EGFR / kinase domain / ONCOPROTEIN
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 / regulation of peptidyl-tyrosine phosphorylation / response to UV-A / tongue development / PLCG1 events in ERBB2 signaling / midgut development / ERBB2-EGFR signaling pathway / digestive tract morphogenesis / hydrogen peroxide metabolic process / morphogenesis of an epithelial fold / PTK6 promotes HIF1A stabilization / 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 / protein tyrosine kinase activator activity / Signaling by ERBB4 / Respiratory syncytial virus (RSV) attachment and entry / 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 / positive regulation of bone resorption / embryonic placenta development / positive regulation of phosphorylation / salivary gland morphogenesis / peptidyl-tyrosine autophosphorylation / positive regulation of peptidyl-serine phosphorylation / 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 / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / GRB2 events in ERBB2 signaling / SHC1 events in ERBB2 signaling / cellular response to epidermal growth factor stimulus / cellular response to dexamethasone stimulus / positive regulation of synaptic transmission, glutamatergic / ossification / positive regulation of DNA repair / neuron projection morphogenesis / positive regulation of superoxide anion generation / positive regulation of epithelial cell proliferation / liver regeneration / epithelial cell proliferation / basal plasma membrane / Signal transduction by L1 / positive regulation of DNA replication / positive regulation of protein localization to plasma membrane / astrocyte activation / phosphatidylinositol 3-kinase/protein kinase B signal transduction / 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 / 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 / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / insulin-like growth factor receptor activity / Signaling by ERBB2 ECD mutants
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 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
1,3-PROPANDIOL / Chem-YY3 / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.551 Å
AuthorsAshtekar, K.D. / Stayrook, S.E. / Lemmon, M.A.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)GR110199 United States
CitationJournal: To Be Published
Title: Comprehensive characterization of EGFR-tyrosine kinase inhibitor interactions probed by hydrogen-deuterium exchange and mass spectrometry (HDX-MS)
Authors: Tsutsui, Y. / Ashtekar, K.D. / Stayrook, S. / Lemmon, M.A.
History
DepositionMay 23, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 28, 2025Provider: repository / Type: Initial release

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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)39,2123
Polymers38,6371
Non-polymers5762
Water362
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)145.916, 145.916, 145.916
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: 38636.656 Da / Num. of mol.: 1
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-PDO / 1,3-PROPANDIOL


Mass: 76.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O2
#3: 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 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication, inhibitor*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 3.7 Å3/Da / Density % sol: 67 % / Description: cubic
Crystal growTemperature: 285.15 K / Method: vapor diffusion, hanging drop / pH: 7.5 / Details: 100 mM HEPES, pH 7.0, 0.6-0.9 Na-K tartrate / PH range: 7.0-7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.97918 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Feb 13, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 2.55→51.59 Å / Num. obs: 16995 / % possible obs: 100 % / Redundancy: 6.7 % / CC1/2: 0.996 / Net I/σ(I): 16
Reflection shellResolution: 2.55→2.8 Å / Num. unique obs: 2807 / CC1/2: 0.32

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Processing

Software
NameVersionClassification
SCALAdata scaling
PHENIX1.14_3260refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.551→51.589 Å / SU ML: 0.38 / Cross valid method: THROUGHOUT / σ(F): 1.54 / Phase error: 24.68 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2452 882 5.19 %
Rwork0.2059 16113 -
obs0.2079 16995 99.99 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 214 Å2 / Biso mean: 96.2519 Å2 / Biso min: 41.27 Å2
Refinement stepCycle: final / Resolution: 2.551→51.589 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2492 0 42 2 2536
Biso mean--104.36 71.03 -
Num. residues----311
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork
2.551-2.71070.30041280.29722679
2.7107-2.920.28231680.26612648
2.92-3.21380.32251400.27342648
3.2138-3.67880.32051290.23632699
3.6788-4.63440.22921660.17892658
4.6344-51.5890.211510.18122781
Refinement TLS params.Method: refined / Origin x: -7.7904 Å / Origin y: -58.4886 Å / Origin z: 24.7827 Å
111213212223313233
T0.656 Å20.004 Å2-0.0652 Å2-0.4886 Å2-0.0403 Å2--0.4901 Å2
L4.0027 °21.4668 °21.5713 °2-1.6781 °20.8627 °2--2.0608 °2
S-0.2179 Å °-0.2639 Å °0.4336 Å °-0.193 Å °-0.055 Å °0.1018 Å °-0.5292 Å °-0.112 Å °0.2446 Å °
Refinement TLS groupSelection details: (chain A and resseq 698:1009)

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