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- PDB-5j9y: EGFR-T790M in complex with pyrazolopyrimidine inhibitor 1b -

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Basic information

Entry
Database: PDB / ID: 5j9y
TitleEGFR-T790M in complex with pyrazolopyrimidine inhibitor 1b
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / tyrosine kinase / covalent inhibitor / drug resistance
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 / ERBB2 Regulates Cell Motility / Developmental Lineage of Mammary Gland Myoepithelial Cells / 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 / MAP kinase kinase kinase activity / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / 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 / cellular response to estradiol stimulus / sperm end piece / 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 / Signaling by ERBB2 TMD/JMD mutants / EGFR downregulation / 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 / positive regulation of fibroblast proliferation / kinase binding / ruffle membrane / epidermal growth factor receptor signaling pathway / cell morphogenesis / Constitutive Signaling by Aberrant PI3K in Cancer / neuron differentiation / 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 / 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-6HL / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsBecker, C. / Engel, J. / Rauh, D.
CitationJournal: Angew.Chem.Int.Ed.Engl. / Year: 2016
Title: Insight into the Inhibition of Drug-Resistant Mutants of the Receptor Tyrosine Kinase EGFR.
Authors: Engel, J. / Becker, C. / Lategahn, J. / Keul, M. / Ketzer, J. / Muhlenberg, T. / Kollipara, L. / Schultz-Fademrecht, C. / Zahedi, R.P. / Bauer, S. / Rauh, D.
History
DepositionApr 11, 2016Deposition site: RCSB / Processing site: PDBE
Revision 1.0Aug 17, 2016Provider: repository / Type: Initial release
Revision 1.1Sep 7, 2016Group: Database references
Revision 1.2Nov 20, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)37,3622
Polymers36,9641
Non-polymers3981
Water21612
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area15490 Å2
MethodPISA
Unit cell
Length a, b, c (Å)144.390, 144.390, 144.390
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: 36963.863 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-6HL / (R)-1-(3-(4-amino-3-(naphthalen-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one


Mass: 398.460 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H22N6O
#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: 3.39 Å3/Da / Density % sol: 63.75 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 100 mM MES, 900 mM - 1100 mM Na/K-tartrate / PH range: 7.0-7.3

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.92045 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Feb 14, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92045 Å / Relative weight: 1
ReflectionResolution: 2.8→45.66 Å / Num. obs: 12497 / % possible obs: 100 % / Observed criterion σ(I): -3 / Redundancy: 20.13 % / Biso Wilson estimate: 64.502 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.161 / Net I/σ(I): 18.11
Reflection shell
Resolution (Å)Highest resolution (Å)Rmerge(I) obsMean I/σ(I) obsDiffraction-ID% possible all
2.8-2.871.9321.691100
2.87-2.951.3592.451100
2.95-3.041.1632.981100
3.04-3.130.9343.761100
3.13-3.230.6465.471100
3.23-3.350.4927.111100
3.35-3.470.3749.051100
3.47-3.620.27512.261100
3.62-3.780.20915.981100
3.78-3.960.15920.271100
3.96-4.170.12724.391100
4.17-4.430.10528.961100
4.43-4.730.08534.231100
4.73-5.110.07936.611100
5.11-5.60.0933.181100
5.6-6.260.08534.141100
6.26-7.230.07238.461100
7.23-8.860.0553.471100
8.86-12.520.03865.231100
12.520.03959.09197.5

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Processing

Software
NameVersionClassification
REFMAC5.8.0135refinement
XSCALE2014data scaling
PDB_EXTRACT3.2data extraction
XDSNov. 2013data reduction
PHASER2.5.1phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.8→45.66 Å / Cor.coef. Fo:Fc: 0.958 / Cor.coef. Fo:Fc free: 0.91 / SU B: 14.558 / SU ML: 0.273 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.567 / ESU R Free: 0.308
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2375 625 5 %RANDOM
Rwork0.1826 ---
obs0.1854 11875 99.97 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 184.02 Å2 / Biso mean: 74.174 Å2 / Biso min: 39.27 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refinement stepCycle: final / Resolution: 2.8→45.66 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2405 0 30 12 2447
Biso mean--62.72 57.57 -
Num. residues----300
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0192497
X-RAY DIFFRACTIONr_bond_other_d0.0070.022443
X-RAY DIFFRACTIONr_angle_refined_deg1.6631.9933381
X-RAY DIFFRACTIONr_angle_other_deg2.5343.0045640
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4975299
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.81224.34106
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.05115458
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.951514
X-RAY DIFFRACTIONr_chiral_restr0.0870.2375
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0212724
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02529
X-RAY DIFFRACTIONr_mcbond_it5.6517.1821199
X-RAY DIFFRACTIONr_mcbond_other5.6427.1771198
X-RAY DIFFRACTIONr_mcangle_it8.87410.7521494
LS refinement shellResolution: 2.801→2.873 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.519 46 -
Rwork0.365 877 -
all-923 -
obs--100 %

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