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- PDB-9ght: Crystal Structure of EGFR-WT in Complex with BI-4020 -

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Basic information

Entry
Database: PDB / ID: 9ght
TitleCrystal Structure of EGFR-WT in Complex with BI-4020
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / EGFR / WT / Exon20
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 / ubiquitin-dependent endocytosis / PLCG1 events in ERBB2 signaling / morphogenesis of an epithelial fold / PTK6 promotes HIF1A stabilization / ERBB2 Activates PTK6 Signaling / digestive tract morphogenesis / ERBB2-EGFR signaling pathway / Signaling by EGFR / eyelid development in camera-type eye / intracellular vesicle / cerebral cortex cell migration / Developmental Lineage of Mammary Gland Myoepithelial Cells / ERBB2 Regulates Cell Motility / protein insertion into membrane / Respiratory syncytial virus (RSV) attachment and entry / protein tyrosine kinase activator activity / Signaling by ERBB4 / negative regulation of epidermal growth factor receptor signaling pathway / PI3K events in ERBB2 signaling / positive regulation of peptidyl-serine phosphorylation / positive regulation of phosphorylation / hair follicle development / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / MAP kinase kinase kinase activity / GAB1 signalosome / embryonic placenta development / positive regulation of G1/S transition of mitotic cell cycle / salivary gland morphogenesis / xenobiotic transport / positive regulation of epidermal growth factor receptor signaling pathway / 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 / epithelial cell proliferation / ossification / cellular response to epidermal growth factor stimulus / basal plasma membrane / positive regulation of DNA replication / positive regulation of epithelial cell proliferation / positive regulation of DNA repair / Signal transduction by L1 / positive regulation of protein localization to plasma membrane / sperm end piece / cellular response to estradiol stimulus / NOTCH3 Activation and Transmission of Signal to the Nucleus / cellular response to amino acid stimulus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / clathrin-coated endocytic vesicle membrane / EGFR downregulation / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII / receptor protein-tyrosine kinase / Signaling by ERBB2 ECD mutants / cell-cell adhesion / negative regulation of protein catabolic process / Signaling by ERBB2 KD Mutants / positive regulation of protein phosphorylation / positive regulation of miRNA transcription / Downregulation of ERBB2 signaling / kinase binding / positive regulation of fibroblast proliferation / ruffle membrane / epidermal growth factor receptor signaling pathway / cell morphogenesis / neuron differentiation / 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 / sperm principal piece / 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 / sperm midpiece / early endosome membrane
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 / 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-XA4 / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsNiggenaber, J. / Mueller, M.P. / Rauh, D.
Funding support Germany, European Union, 4items
OrganizationGrant numberCountry
German Federal Ministry for Education and Research01ZX2201B Germany
European Regional Development FundEFRE-800400European Union
Other privateEx-2021-0033
Other governmentNW21-062C
CitationJournal: to be published
Title: Selective Targeting of EGFR-Exon20 Insertion Mutations in Non-Small Cell Lung Cancer with Nazartinib and BI-4020 Inspired Hybrid Inhibitors
Authors: Grabe, T. / Jeyakumar, K. / Niggenaber, J. / Grabe, B. / Koska, S. / Zischinsky, M. / Unger, A. / Weisner, J. / Arndt, A. / Mueller, M.P. / Rauh, D.
History
DepositionAug 16, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 4, 2026Provider: 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)38,4182
Polymers37,8761
Non-polymers5431
Water543
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area14780 Å2
Unit cell
Length a, b, c (Å)147.650, 147.650, 147.650
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: 37875.754 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-XA4 / (20R)-10,15,20-trimethyl-2-[(4-methylpiperazin-1-yl)methyl]-18,19,20,21-tetrahydro-15H,17H-12,8-(metheno)pyrazolo[3',4':2,3][1,5,10,12]oxatriazacycloheptadecino[12,11-a]benzimidazol-7(6H)-one


Mass: 542.675 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H38N8O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 3 / 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: 3.54 Å3/Da / Density % sol: 65.26 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 1.5 K-Na-tartrate, 100 mM Na-MES (pH 7.0), 4.3 mg/mL EGFR-WT (im 100 mM NaCl, 25 mM Tris-HCl, 10 % glycerol, 1 mM TCEP, pH 8.0, 1 ul reservoir + 1 ul solution) Soaking-Experiment

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Jun 9, 2021
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.6→42.62 Å / Num. obs: 16618 / % possible obs: 99.9 % / Redundancy: 10.13 % / CC1/2: 1 / Rrim(I) all: 0.05 / Net I/σ(I): 20.07
Reflection shellResolution: 2.6→2.7 Å / Mean I/σ(I) obs: 2.68 / Num. unique obs: 1744 / CC1/2: 0.801 / Rrim(I) all: 1.038 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.6→42.62 Å / SU ML: 0.27 / Cross valid method: THROUGHOUT / σ(F): 1.37 / Phase error: 27.25 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2367 831 5 %
Rwork0.1975 15786 -
obs0.1995 16617 99.98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 142.89 Å2 / Biso mean: 78.5974 Å2 / Biso min: 51.6 Å2
Refinement stepCycle: final / Resolution: 2.6→42.62 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2341 0 40 3 2384
Biso mean--80.21 72.63 -
Num. residues----300
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 6 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all
2.6-2.760.31231360.263825942730
2.76-2.980.30211380.29726162754
2.98-3.270.31281370.264326052742
3.28-3.750.25641370.234126042741
3.75-4.720.18981400.167226552795
4.73-42.620.22951430.169727122855
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
13.74980.06640.80010.9146-1.64193.9392-0.0080.7306-0.09070.6650.10030.7315-0.8750.41050.04260.71620.13140.05610.7865-0.08230.835456.08039.975334.4847
22.205-0.99170.44861.6203-2.03554.1160.1540.0850.64650.027-0.10091.0297-0.088-0.6384-0.10280.6260.1155-0.03450.7832-0.10420.709152.04018.492325.7164
30.4915-0.10220.38092.206-0.56553.0187-0.05960.2036-0.0104-0.16770.06720.3209-0.2102-0.5428-0.09160.62850.08430.00550.7014-0.10840.763155.211.615335.3915
43.2313-0.725-0.15213.44820.51411.51040.06580.13510.1236-0.2401-0.19560.2762-0.2111-0.33420.12560.48280.0711-0.01870.544-0.04130.511261.8707-7.113920.9019
54.1087-0.47460.646.1651-1.33345.1713-0.3114-0.634-0.15410.6487-0.12160.30270.5879-0.67310.21250.84990.00710.14810.9235-0.14940.742257.291-13.374739.9628
61.5302-0.1156-2.15730.1930.15754.0563-0.2003-0.1801-0.07050.8874-0.0390.1041-0.2006-0.12130.39510.8635-0.05580.20290.8726-0.08710.938353.2574-22.270833.3609
70.4129-0.4693-0.80073.44180.16573.0793-0.04080.0611-0.0928-0.1393-0.32760.69950.5943-0.37550.36590.69630.07330.04170.738-0.11020.753157.5423-20.101921.2755
81.0473-0.09631.02021.30310.38191.179-0.224-0.35990.0540.208-0.04070.85020.642-0.46110.32850.8124-0.03020.10050.77-0.1650.676155.7897-29.126420.4192
91.13210.68290.02642.9991.43210.8371-0.1716-0.6656-0.18620.6008-0.21650.18490.22260.030.31570.72120.05530.04170.7366-0.04030.703667.0357-26.58224.7269
102.2238-0.3769-1.13723.53772.49866.0541-0.3330.0674-0.0418-0.2176-0.0539-0.31030.10780.78350.01640.68570.0657-0.03750.57450.00570.737775.2454-17.224818.3988
111.82740.5427-1.43011.5455-0.85431.10880.19510.30190.5266-0.2761-0.0735-0.2381-0.7023-0.2397-0.20540.80430.2475-0.18340.91280.07990.653566.34912.391816.2752
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 697 through 717 )A697 - 717
2X-RAY DIFFRACTION2chain 'A' and (resid 718 through 752 )A718 - 752
3X-RAY DIFFRACTION3chain 'A' and (resid 753 through 786 )A753 - 786
4X-RAY DIFFRACTION4chain 'A' and (resid 787 through 853 )A787 - 853
5X-RAY DIFFRACTION5chain 'A' and (resid 854 through 873 )A854 - 873
6X-RAY DIFFRACTION6chain 'A' and (resid 874 through 892 )A874 - 892
7X-RAY DIFFRACTION7chain 'A' and (resid 893 through 919 )A893 - 919
8X-RAY DIFFRACTION8chain 'A' and (resid 920 through 940 )A920 - 940
9X-RAY DIFFRACTION9chain 'A' and (resid 941 through 960 )A941 - 960
10X-RAY DIFFRACTION10chain 'A' and (resid 961 through 977 )A961 - 977
11X-RAY DIFFRACTION11chain 'A' and (resid 978 through 1019 )A978 - 1019

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