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- PDB-7u99: EGFR kinase in complex with a macrocyclic inhibitor -

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Basic information

Entry
Database: PDB / ID: 7u99
TitleEGFR kinase in complex with a macrocyclic inhibitor
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / EGFR / kinase / macrocycle / inhibitor / TRANSFERASE / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


response to hydroxyisoflavone / multivesicular body, internal vesicle lumen / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / positive regulation of protein kinase C activity / diterpenoid metabolic process / Shc-EGFR complex / ovulation cycle / Inhibition of Signaling by Overexpressed EGFR / epidermal growth factor receptor activity ...response to hydroxyisoflavone / multivesicular body, internal vesicle lumen / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / positive regulation of protein kinase C activity / diterpenoid metabolic process / Shc-EGFR complex / ovulation cycle / Inhibition of Signaling by Overexpressed EGFR / epidermal growth factor receptor activity / EGFR interacts with phospholipase C-gamma / positive regulation of mucus secretion / response to UV-A / epidermal growth factor binding / PLCG1 events in ERBB2 signaling / tongue development / midgut development / ERBB2-EGFR signaling pathway / hydrogen peroxide metabolic process / PTK6 promotes HIF1A stabilization / digestive tract morphogenesis / morphogenesis of an epithelial fold / ERBB2 Activates PTK6 Signaling / intracellular vesicle / Signaling by EGFR / response to cobalamin / transmembrane receptor protein tyrosine kinase activator activity / protein tyrosine kinase activator activity / negative regulation of epidermal growth factor receptor signaling pathway / Signaling by ERBB4 / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / eyelid development in camera-type eye / protein insertion into membrane / cerebral cortex cell migration / ERBB2 Regulates Cell Motility / Respiratory syncytial virus (RSV) attachment and entry / regulation of JNK cascade / : / PI3K events in ERBB2 signaling / positive regulation of cyclin-dependent protein serine/threonine kinase activity / negative regulation of mitotic cell cycle / hair follicle development / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / MAP kinase kinase kinase activity / embryonic placenta development / positive regulation of bone resorption / positive regulation of G1/S transition of mitotic cell cycle / GAB1 signalosome / salivary gland morphogenesis / peptidyl-tyrosine autophosphorylation / regulation of peptidyl-tyrosine phosphorylation / positive regulation of phosphorylation / positive regulation of glial cell proliferation / positive regulation of vasoconstriction / Signaling by ERBB2 / cellular response to epidermal growth factor stimulus / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / cellular response to cadmium ion / positive regulation of DNA repair / EGFR Transactivation by Gastrin / GRB2 events in ERBB2 signaling / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / transmembrane receptor protein tyrosine kinase activity / SHC1 events in ERBB2 signaling / positive regulation of synaptic transmission, glutamatergic / ossification / cellular response to dexamethasone stimulus / basal plasma membrane / neurogenesis / regulation of ERK1 and ERK2 cascade / neuron projection morphogenesis / positive regulation of superoxide anion generation / positive regulation of DNA replication / epithelial cell proliferation / Signal transduction by L1 / cellular response to estradiol stimulus / NOTCH3 Activation and Transmission of Signal to the Nucleus / positive regulation of epithelial cell proliferation / astrocyte activation / liver regeneration / positive regulation of protein localization to plasma membrane / EGFR downregulation / cellular response to amino acid stimulus / positive regulation of smooth muscle cell proliferation / Signaling by ERBB2 TMD/JMD mutants / positive regulation of MAP kinase activity / lung development / clathrin-coated endocytic vesicle membrane / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / epidermal growth factor receptor signaling pathway / negative regulation of protein catabolic process / receptor protein-tyrosine kinase / Downregulation of ERBB2 signaling / kinase binding / ruffle membrane / positive regulation of miRNA transcription / cell-cell adhesion
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
CITRATE ANION / Chem-M0R / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsBeyett, T.S. / Eck, M.J.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)5F32CA247198-02 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)5R01CA116020-15 United States
CitationJournal: J.Med.Chem. / Year: 2022
Title: Macrocyclization of Quinazoline-Based EGFR Inhibitors Leads to Exclusive Mutant Selectivity for EGFR L858R and Del19.
Authors: Amrhein, J.A. / Beyett, T.S. / Feng, W.W. / Kramer, A. / Weckesser, J. / Schaeffner, I.K. / Rana, J.K. / Janne, P.A. / Eck, M.J. / Knapp, S. / Hanke, T.
History
DepositionMar 10, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 23, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 30, 2022Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Dec 21, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Oct 25, 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)38,2573
Polymers37,6361
Non-polymers6212
Water43224
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)145.532, 145.532, 145.532
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: 37636.441 Da / Num. of mol.: 1 / Fragment: kinase domain, residues 695-1022
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EGFR, ERBB, ERBB1, HER1 / Plasmid: pTriEX / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P00533, receptor protein-tyrosine kinase
#2: Chemical ChemComp-M0R / 19-chloro-22-methoxy-8,9,11,12,14,15-hexahydro-21H-4,6-ethenopyrimido[5,4-m][1,4,7,10,15]benzotetraoxazacycloheptadecine


Mass: 431.869 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H22ClN3O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-FLC / CITRATE ANION


Mass: 189.100 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H5O7
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 24 / 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: 3.41 Å3/Da / Density % sol: 63.95 % / Mosaicity: 0.062 °
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-C / Wavelength: 0.97918 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jul 23, 2021
RadiationMonochromator: Double Crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 2.5→102.91 Å / Num. obs: 17751 / % possible obs: 99.1 % / Redundancy: 5.1 % / Biso Wilson estimate: 60.09 Å2 / Rpim(I) all: 0.048 / Rrim(I) all: 0.112 / Net I/σ(I): 10.1 / Num. measured all: 90487
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Mean I/σ(I) obsNum. measured allNum. unique obsRpim(I) allRrim(I) all% possible all
2.5-2.545.2146799000.4971.16499.6
6.79-102.994.929.545029160.0250.05895.1

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Processing

Software
NameVersionClassification
xia2data scaling
PHENIX1.20.1_4487refinement
PDB_EXTRACT3.27data extraction
xia2data reduction
PHASERphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6VHP

6vhp


Resolution: 2.5→102.91 Å / SU ML: 0.32 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 25.6 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2139 993 5.59 %
Rwork0.187 16755 -
obs0.1886 17748 99.13 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 161.18 Å2 / Biso mean: 69.706 Å2 / Biso min: 34.98 Å2
Refinement stepCycle: final / Resolution: 2.5→102.91 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2423 0 43 24 2490
Biso mean--71.82 60.38 -
Num. residues----304
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 (%)
2.5-2.630.32371330.289423982531100
2.63-2.80.31821210.258324292550100
2.8-3.010.26271290.24323862515100
3.01-3.320.26691400.231224062546100
3.32-3.80.23331760.18452339251599
3.8-4.780.18111480.15332392254099
4.79-102.910.17231460.16092405255197
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)
14.71371.3083-1.21845.3651-0.51299.32610.0125-0.26060.82130.3926-0.0672-0.2171-1.48620.42530.05860.5619-0.0923-0.11960.4313-0.03290.4735.8855-52.873431.735
27.02810.21841.0293.56580.56444.0217-0.17-0.57210.72280.123-0.13790.2183-0.518-0.20860.29290.4128-0.0133-0.05830.321-0.0880.338-15.0294-60.906523.2784
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 694 through 791 )A694 - 791
2X-RAY DIFFRACTION2chain 'A' and (resid 792 through 1018 )A792 - 1018

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