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- PDB-6d8e: Discovery of a Highly Potent and Broadly Effective EGFR and HER2 ... -

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Basic information

Entry
Database: PDB / ID: 6d8e
TitleDiscovery of a Highly Potent and Broadly Effective EGFR and HER2 Exon 20 Insertion Mutant Inhibitor
ComponentsEpidermal growth factor receptor
KeywordsTransferase/Transferase Inhibitor / EGFR / Inhibitor / SIGNALING PROTEIN / 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 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-FZP / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.537 Å
AuthorsPark, E. / Eck, M.J.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)CA116020 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)CA221830 United States
CitationJournal: Angew. Chem. Int. Ed. Engl. / Year: 2018
Title: Discovery of a Highly Potent and Broadly Effective Epidermal Growth Factor Receptor and HER2 Exon 20 Insertion Mutant Inhibitor.
Authors: Jang, J. / Son, J. / Park, E. / Kosaka, T. / Saxon, J.A. / De Clercq, D.J.H. / Choi, H.G. / Tanizaki, J. / Eck, M.J. / Janne, P.A. / Gray, N.S.
History
DepositionApr 26, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 18, 2018Provider: repository / Type: Initial release
Revision 1.1Aug 15, 2018Group: Data collection / Database references / Category: citation / citation_author / Item: _citation.title / _citation_author.name
Revision 1.2Sep 12, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Dec 4, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.5Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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)37,7942
Polymers37,3041
Non-polymers4901
Water21612
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)146.572, 146.572, 146.572
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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: 37304.129 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-FZP / (4-fluorophenyl)methyl {2-[(1-methyl-1H-pyrazol-3-yl)amino]pyrimidin-4-yl}[3-(propanoylamino)phenyl]carbamate


Mass: 489.502 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H24FN7O3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 12 / Source method: isolated from a natural source / Formula: H2O
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: 3.5 Å3/Da / Density % sol: 64.86 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / Details: 0.1 M MES(pH 6.5), 1.0 M sodium citrate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.987 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Aug 19, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 2.537→103.64 Å / Num. obs: 17449 / % possible obs: 99.7 % / Redundancy: 4.8 % / Net I/σ(I): 14.2
Reflection shellResolution: 2.537→2.65 Å / Redundancy: 4.7 % / Num. unique obs: 2093 / % possible all: 98.5

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Processing

Software
NameVersionClassification
PHENIX(1.13_2998: ???)refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4ZAU

4zau


Resolution: 2.537→59.838 Å / SU ML: 0.41 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 28.11
RfactorNum. reflection% reflection
Rfree0.2426 1740 10.04 %
Rwork0.2087 --
obs0.2122 17337 99.02 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.537→59.838 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2400 0 0 12 2412
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0092452
X-RAY DIFFRACTIONf_angle_d1.0383326
X-RAY DIFFRACTIONf_dihedral_angle_d11.9531466
X-RAY DIFFRACTIONf_chiral_restr0.055378
X-RAY DIFFRACTIONf_plane_restr0.007417
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.5369-2.61160.36011360.32821191X-RAY DIFFRACTION91
2.6116-2.69590.33551450.30681271X-RAY DIFFRACTION99
2.6959-2.79220.35391450.30491286X-RAY DIFFRACTION100
2.7922-2.9040.38471450.29751303X-RAY DIFFRACTION100
2.904-3.03620.33161420.2541294X-RAY DIFFRACTION100
3.0362-3.19620.30561450.26071316X-RAY DIFFRACTION100
3.1962-3.39650.29111430.23181292X-RAY DIFFRACTION100
3.3965-3.65870.2881410.22041321X-RAY DIFFRACTION100
3.6587-4.02680.2381470.18171310X-RAY DIFFRACTION100
4.0268-4.60930.21541490.17051316X-RAY DIFFRACTION100
4.6093-5.80650.19621430.18781335X-RAY DIFFRACTION100
5.8065-59.85440.18431590.18141362X-RAY DIFFRACTION99

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