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- PDB-7b85: Crystal Structure of EGFR-WT in Complex with TAK-788 -

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Basic information

Entry
Database: PDB / ID: 7b85
TitleCrystal Structure of EGFR-WT in Complex with TAK-788
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / EGFR / WT / Exon20 / covalent
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 / 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-R28 / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsNiggenaber, J. / Mueller, M.P. / Rauh, D.
Funding support Germany, 3items
OrganizationGrant numberCountry
German Federal Ministry for Education and ResearchBMBF 01GS08104 Germany
German Federal Ministry for Education and ResearchBMBF 01ZX1303C Germany
European Regional Development FundEFRE-800400 Germany
CitationJournal: J.Med.Chem. / Year: 2022
Title: Insight into Targeting Exon20 Insertion Mutations of the Epidermal Growth Factor Receptor with Wild Type-Sparing Inhibitors.
Authors: Lategahn, J. / Tumbrink, H.L. / Schultz-Fademrecht, C. / Heimsoeth, A. / Werr, L. / Niggenaber, J. / Keul, M. / Parmaksiz, F. / Baumann, M. / Menninger, S. / Zent, E. / Landel, I. / Weisner, ...Authors: Lategahn, J. / Tumbrink, H.L. / Schultz-Fademrecht, C. / Heimsoeth, A. / Werr, L. / Niggenaber, J. / Keul, M. / Parmaksiz, F. / Baumann, M. / Menninger, S. / Zent, E. / Landel, I. / Weisner, J. / Jeyakumar, K. / Heyden, L. / Russ, N. / Muller, F. / Lorenz, C. / Bragelmann, J. / Spille, I. / Grabe, T. / Muller, M.P. / Heuckmann, J.M. / Klebl, B.M. / Nussbaumer, P. / Sos, M.L. / Rauh, D.
History
DepositionDec 12, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 23, 2022Provider: repository / Type: Initial release
Revision 1.1May 11, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2May 25, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Oct 5, 2022Group: Structure summary / Category: chem_comp / Item: _chem_comp.pdbx_synonyms
Revision 1.4Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.5Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)38,6593
Polymers37,8761
Non-polymers7832
Water1086
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area280 Å2
ΔGint2 kcal/mol
Surface area14560 Å2
MethodPISA
Unit cell
Length a, b, c (Å)144.280, 144.280, 144.280
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-1206-

HOH

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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-R28 / propan-2-yl 2-[[4-[2-(dimethylamino)ethyl-methyl-amino]-2-methoxy-5-(propanoylamino)phenyl]amino]-4-(1-methylindol-3-yl)pyrimidine-5-carboxylate / Mobocertinib, bound form


Mass: 587.712 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H41N7O4 / Feature type: SUBJECT OF INVESTIGATION / Comment: inhibitor*YM
#3: 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
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 6 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 3.3 Å3/Da / Density % sol: 62.77 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 1.6 K-Na-tartrate, 100 mM Na-MES (pH 7.0), 6.2 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: 0.9999 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Aug 31, 2020
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9999 Å / Relative weight: 1
ReflectionResolution: 2.5→46.63 Å / Num. obs: 17435 / % possible obs: 100 % / Redundancy: 10.34 % / CC1/2: 0.998 / Rrim(I) all: 0.096 / Net I/σ(I): 14.93
Reflection shellResolution: 2.5→2.6 Å / Redundancy: 10.35 % / Mean I/σ(I) obs: 2.01 / Num. unique obs: 1917 / CC1/2: 0.635 / Rrim(I) all: 1.636 / % possible all: 99.9

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Processing

Software
NameVersionClassification
PHENIX1.18.2_3874refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6S8A

6s8a


Resolution: 2.5→45.63 Å / SU ML: 0.32 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 27.89 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.244 871 5 %
Rwork0.2147 16564 -
obs0.2161 17435 99.96 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 197.3 Å2 / Biso mean: 82.8126 Å2 / Biso min: 56.18 Å2
Refinement stepCycle: final / Resolution: 2.5→45.63 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2415 0 55 6 2476
Biso mean--91.19 86.24 -
Num. residues----312
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
2.5-2.660.32631440.306827462890
2.66-2.860.33591430.295227092852
2.86-3.150.29711440.276327402884
3.15-3.60.2951450.248327612906
3.61-4.540.21261460.192827652911
4.55-45.630.21831490.186728432992
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)
11.42561.3861-2.76643.4016-1.19986.3726-0.12890.19120.091-0.50760.6061-0.0724-0.08360.0726-0.45180.7513-0.156-0.05320.8180.00540.77327.8486-52.364230.9831
23.15240.60291.25610.86570.0034.1661-0.20590.14710.59890.6259-0.0058-0.8344-0.70590.16640.270.8236-0.1995-0.00220.6607-0.02170.684111.7062-52.274725.0818
32.7011-0.808-0.24871.4769-0.22662.9245-0.04160.14290.342-0.1444-0.0969-0.1402-0.43770.0150.03450.6253-0.0609-0.09520.6954-0.03970.62.2458-53.844234.2267
47.32132.07281.04344.62170.74721.5166-0.28930.52290.3361-0.20270.0861-0.12-0.14730.33580.18040.5655-0.048-0.04330.62930.02140.5165-6.6144-60.521120.1117
52.09770.1496-0.61862.81130.42281.0977-0.1155-0.84280.55470.5394-0.34790.153-0.46-0.10610.3560.8114-0.0185-0.12770.8634-0.12380.812-16.9293-53.75535.1499
64.3866-0.58971.48962.9866-0.14933.0085-0.28060.02880.3666-0.0114-0.17660.0729-0.4859-0.4030.44890.5819-0.0562-0.06450.6969-0.05270.5295-22.495-61.567520.3288
72.99030.3951-1.90081.509-2.95396.1855-0.30480.120.1354-0.0975-0.1763-0.4671-0.4590.8460.37540.8714-0.05290.07050.7978-0.04170.6562-0.8401-62.02567.8864
88.0131-1.5756-1.25531.80981.06971.1198-0.52151.3248-0.2046-0.90210.5905-0.0984-0.363-0.129-0.05741.0489-0.20270.04130.9783-0.0360.798814.4693-60.837419.243
92.67111.25351.77752.15591.94541.97053.1562-1.21948.38746.8143-2.128428.4321-3.7221-6.3327-0.79111.8460.69960.08072.25290.2312.245815.6143-65.614834.5775
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 697 through 724 )A697 - 724
2X-RAY DIFFRACTION2chain 'A' and (resid 725 through 752 )A725 - 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 892 )A854 - 892
6X-RAY DIFFRACTION6chain 'A' and (resid 893 through 977 )A893 - 977
7X-RAY DIFFRACTION7chain 'A' and (resid 978 through 1002 )A978 - 1002
8X-RAY DIFFRACTION8chain 'A' and (resid 1003 through 1018 )A0
9X-RAY DIFFRACTION9chain 'A' and (resid 1019 through 1019 )A0

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