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- PDB-8f1x: EGFR kinase in complex with mobocertinib (TAK-788) -

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Basic information

Entry
Database: PDB / ID: 8f1x
TitleEGFR kinase in complex with mobocertinib (TAK-788)
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / EGFR / kinase / inhibitor / TRANSFERASE / TRANSFERASE-TRANSFERASE INHIBITOR complex
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
Chem-R28 / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsBeyett, T.S. / Eck, M.J.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)5R01CA116020-16 United States
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2024
Title: Biochemical analysis of EGFR exon20 insertion variants insASV and insSVD and their inhibitor sensitivity.
Authors: Zhao, H. / Beyett, T.S. / Jiang, J. / Rana, J.K. / Schaeffner, I.K. / Santana, J. / Janne, P.A. / Eck, M.J.
History
DepositionNov 6, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 8, 2023Provider: repository / Type: Initial release
Revision 1.1Nov 6, 2024Group: Database references / Structure summary
Category: citation / citation_author ...citation / citation_author / pdbx_entry_details / pdbx_modification_feature
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _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)38,2242
Polymers37,6361
Non-polymers5881
Water81145
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)145.431, 145.431, 145.431
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number197
Space group name H-MI23
Components on special symmetry positions
IDModelComponents
11A-1245-

HOH

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Components

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


Mass: 37636.441 Da / Num. of mol.: 1 / Fragment: kinase domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EGFR, ERBB, ERBB1, HER1 / Cell line (production host): Sf9 / 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: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 45 / 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: 3.41 Å3/Da / Density % sol: 63.88 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.5 / Details: 0.1 M MES pH=6.5, 1.1 M Sodium Citrate

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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 14, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 2.3→51.42 Å / Num. obs: 22536 / % possible obs: 98.6 % / Redundancy: 5.2 % / CC1/2: 0.998 / Rmerge(I) obs: 0.074 / Rpim(I) all: 0.035 / Rrim(I) all: 0.082 / Net I/σ(I): 12.8 / Num. measured all: 117782
Reflection shellResolution: 2.3→2.34 Å / % possible obs: 100 % / Redundancy: 5.2 % / Rmerge(I) obs: 0.777 / Num. measured all: 5954 / Num. unique obs: 1146 / CC1/2: 0.629 / Rpim(I) all: 0.373 / Rrim(I) all: 0.865 / Net I/σ(I) obs: 1.1

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Processing

Software
NameVersionClassification
xia2data scaling
PHENIX1.20.1refinement
xia2data reduction
PHASERphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2GS2

2gs2


Resolution: 2.3→51.42 Å / SU ML: 0.29 / Cross valid method: FREE R-VALUE / σ(F): 1.38 / Phase error: 27.98 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2259 1131 5.02 %
Rwork0.2037 --
obs0.2048 22532 98.53 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.3→51.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2540 0 43 45 2628
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0022653
X-RAY DIFFRACTIONf_angle_d0.4933592
X-RAY DIFFRACTIONf_dihedral_angle_d14.731003
X-RAY DIFFRACTIONf_chiral_restr0.042392
X-RAY DIFFRACTIONf_plane_restr0.003453
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3-2.40.32311570.28242660X-RAY DIFFRACTION100
2.41-2.530.29711600.26492681X-RAY DIFFRACTION100
2.53-2.690.2921580.26852656X-RAY DIFFRACTION99
2.69-2.90.30581160.26912677X-RAY DIFFRACTION99
2.9-3.190.29651300.24462692X-RAY DIFFRACTION99
3.19-3.650.25151420.22272679X-RAY DIFFRACTION99
3.65-4.60.17911170.16622690X-RAY DIFFRACTION98
4.6-51.420.1781510.16722666X-RAY DIFFRACTION95
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)
13.3878-2.89672.28928.6116-4.2212.8408-0.0766-0.2303-0.45790.84970.31110.3989-0.69580.044-0.29880.60380.17450.07680.5686-0.07480.49979.397755.5904-33.6429
29.0221.26271.73647.23492.0077.6657-0.47280.0387-1.1318-0.36470.3252-0.40741.38630.1280.04130.7870.11860.10810.41920.01510.43279.20950.5753-25.4478
34.6298-2.3736-2.27372.59721.46224.2034-0.3437-0.1227-0.40780.20960.22480.15080.55340.08960.17120.3980.00170.05220.35610.01120.3633-3.069158.3977-24.9184
47.53-0.08211.20585.00322.26127.5998-0.11351.0655-0.515-0.5196-0.14830.09650.3693-0.16450.13710.49540.04350.18110.5915-0.07490.4677-9.873858.888-31.763
54.518-0.2861-1.11973.02621.56474.8214-0.32820.3767-0.8602-0.0195-0.29060.37680.6875-0.58910.55710.41-0.03140.12190.482-0.09720.4545-22.653960.2092-23.0142
66.3446-4.3806-3.07052.96151.85551.8463-0.4467-1.54080.22750.54780.3002-0.83040.80891.27050.16940.79830.2258-0.0421.23590.18270.7279-4.102763.4439-5.724
75.2214-1.14713.43145.8935-1.54032.5114-0.6063-1.4164-0.78021.12580.7913-0.40320.85421.24160.14350.80080.35260.00110.94160.06940.5514.439760.5979-19.1891
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 696 through 717 )
2X-RAY DIFFRACTION2chain 'A' and (resid 718 through 752 )
3X-RAY DIFFRACTION3chain 'A' and (resid 753 through 830 )
4X-RAY DIFFRACTION4chain 'A' and (resid 831 through 873 )
5X-RAY DIFFRACTION5chain 'A' and (resid 874 through 977 )
6X-RAY DIFFRACTION6chain 'A' and (resid 978 through 1001 )
7X-RAY DIFFRACTION7chain 'A' and (resid 1002 through 1018 )

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