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- PDB-6lub: Crystal Structure of EGFR(L858R/T790M/C797S) in complex with CH7233163 -

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Basic information

Entry
Database: PDB / ID: 6lub
TitleCrystal Structure of EGFR(L858R/T790M/C797S) in complex with CH7233163
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / PROTEIN KINASE / INHIBITOR / TRANSFERASE-TRANSFERASE INHIBITOR COMPLEX / TRANSFERASE
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 / epidermal growth factor receptor activity / EGFR interacts with phospholipase C-gamma / regulation of peptidyl-tyrosine phosphorylation / epidermal growth factor binding / response to UV-A ...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 / epidermal growth factor receptor activity / EGFR interacts with phospholipase C-gamma / regulation of peptidyl-tyrosine phosphorylation / epidermal growth factor binding / response to UV-A / PLCG1 events in ERBB2 signaling / ERBB2-EGFR signaling pathway / morphogenesis of an epithelial fold / PTK6 promotes HIF1A stabilization / Signaling by EGFR / ERBB2 Activates PTK6 Signaling / digestive tract morphogenesis / intracellular vesicle / eyelid development in camera-type eye / negative regulation of epidermal growth factor receptor signaling pathway / cerebral cortex cell migration / protein insertion into membrane / ERBB2 Regulates Cell Motility / protein tyrosine kinase activator activity / Respiratory syncytial virus (RSV) attachment and entry / Signaling by ERBB4 / PI3K events in ERBB2 signaling / positive regulation of phosphorylation / positive regulation of peptidyl-serine phosphorylation / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / hair follicle development / positive regulation of G1/S transition of mitotic cell cycle / MAP kinase kinase kinase activity / GAB1 signalosome / embryonic placenta development / salivary gland morphogenesis / Signaling by ERBB2 / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / GRB2 events in EGFR signaling / transmembrane receptor protein tyrosine kinase activity / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / GRB2 events in ERBB2 signaling / SHC1 events in ERBB2 signaling / ossification / basal plasma membrane / cellular response to epidermal growth factor stimulus / positive regulation of DNA repair / positive regulation of DNA replication / epithelial cell proliferation / positive regulation of epithelial cell proliferation / Signal transduction by L1 / positive regulation of protein localization to plasma membrane / cellular response to amino acid stimulus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / NOTCH3 Activation and Transmission of Signal to the Nucleus / cellular response to estradiol stimulus / clathrin-coated endocytic vesicle membrane / EGFR downregulation / Signaling by ERBB2 TMD/JMD mutants / cell-cell adhesion / Constitutive Signaling by EGFRvIII / receptor protein-tyrosine kinase / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / negative regulation of protein catabolic process / positive regulation of miRNA transcription / epidermal growth factor receptor signaling pathway / kinase binding / ruffle membrane / Downregulation of ERBB2 signaling / positive regulation of fibroblast proliferation / cell morphogenesis / neuron differentiation / positive regulation of protein phosphorylation / Constitutive Signaling by Aberrant PI3K in Cancer / HCMV Early Events / actin filament binding / cell junction / transmembrane signaling receptor activity / positive regulation of canonical Wnt signaling pathway / PIP3 activates AKT signaling / Cargo recognition for clathrin-mediated endocytosis / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / Clathrin-mediated endocytosis / ATPase binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / virus receptor activity / RAF/MAP kinase cascade / positive regulation of cell growth / protein tyrosine kinase activity / double-stranded DNA binding / early endosome membrane / protein phosphatase binding / nuclear membrane / basolateral plasma membrane / learning or memory / cell surface receptor signaling pathway / Extra-nuclear estrogen signaling / positive regulation of ERK1 and ERK2 cascade
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
Chem-EUX / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.315 Å
AuthorsKawauchi, H. / Fukami, T.A. / Sato, S. / Endo, M. / Torizawa, T. / Kashima, K. / Chiba, T. / Sakamoto, H.
CitationJournal: Mol.Cancer Ther. / Year: 2020
Title: CH7233163 Overcomes Osimertinib-Resistant EGFR-Del19/T790M/C797S Mutation.
Authors: Kashima, K. / Kawauchi, H. / Tanimura, H. / Tachibana, Y. / Chiba, T. / Torizawa, T. / Sakamoto, H.
History
DepositionJan 27, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 7, 2020Provider: repository / Type: Initial release
Revision 1.1Aug 25, 2021Group: Database references / Category: citation / database_2
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)38,0022
Polymers37,3321
Non-polymers6701
Water1,65792
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area14420 Å2
Unit cell
Length a, b, c (Å)144.299, 144.299, 144.299
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number197
Space group name H-MI23
Components on special symmetry positions
IDModelComponents
11A-1291-

HOH

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Components

#1: Protein Epidermal growth factor receptor / Proto-oncogene c-ErbB-1 / Receptor tyrosine-protein kinase erbB-1


Mass: 37332.152 Da / Num. of mol.: 1 / Fragment: kinase domain / Mutation: L858R, T790M, C797S, E865A, E866A, K867A
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-EUX / N-[2-(1-cyclopropylsulfonylpyrazol-4-yl)pyrimidin-4-yl]-7-(4-methylpiperazin-1-yl)-5-propan-2-yl-9-[2,2,2-tris(fluoranyl)ethoxy]pyrido[4,3-b]indol-3-amine


Mass: 669.720 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H34F3N9O3S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 92 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 3.35 Å3/Da / Density % sol: 63.32 % / Mosaicity: 0.08 °
Crystal growTemperature: 294 K / Method: vapor diffusion / pH: 7
Details: 1.0 M Succinic Acid, 1.0 %(w/v) Polyethylene glycol monomethyl ether 2000, 0.1 M HEPES

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL45XU / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jun 19, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.315→72.15 Å / Num. obs: 21099 / % possible obs: 96.31 % / Redundancy: 19.89 % / CC1/2: 0.9994 / Rmerge(I) obs: 0.152 / Rpim(I) all: 0.035 / Rrim(I) all: 0.156 / Net I/σ(I): 17.621
Reflection shell
Resolution (Å)Redundancy (%)Num. unique obsCC1/2Diffraction-ID% possible all
2.315-2.38521.4710580.4817157.44
6.519-72.1518.1410540.99971100

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Processing

Software
NameVersionClassification
PHENIX1.17_3644refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
DIMPLEphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5EM7

5em7


Resolution: 2.315→72.15 Å / SU ML: 0.33 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 23.64
RfactorNum. reflection% reflectionSelection details
Rfree0.2255 1025 4.86 %RANDOM
Rwork0.1856 ---
obs0.1874 21098 96.23 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 139 Å2 / Biso mean: 60.6602 Å2 / Biso min: 35.12 Å2
Refinement stepCycle: final / Resolution: 2.315→72.15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2345 0 47 92 2484
Biso mean--89.61 58.5 -
Num. residues----301
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 7

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.31-2.440.31881230.27782133225673
2.44-2.590.29631480.259129723120100
2.59-2.790.31741650.235729413106100
2.79-3.070.25691800.205129473127100
3.07-3.510.24941380.191829813119100
3.52-4.420.17431540.157429763130100
4.43-72.150.20271170.172931233240100

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