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- PDB-5gtz: Crystal structure of EGFR 696-1022 T790M in complex with JTS-1-39 -

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Basic information

Entry
Database: PDB / ID: 5gtz
TitleCrystal structure of EGFR 696-1022 T790M in complex with JTS-1-39
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / EGFR / T790M / JTS-1-39 / inhibitor
Function / homology
Function and homology information


response to hydroxyisoflavone / multivesicular body, internal vesicle lumen / positive regulation of protein kinase C activity / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / diterpenoid metabolic process / Shc-EGFR complex / ovulation cycle / tongue development / Inhibition of Signaling by Overexpressed EGFR ...response to hydroxyisoflavone / multivesicular body, internal vesicle lumen / positive regulation of protein kinase C activity / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / diterpenoid metabolic process / Shc-EGFR complex / ovulation cycle / tongue development / Inhibition of Signaling by Overexpressed EGFR / epidermal growth factor receptor activity / EGFR interacts with phospholipase C-gamma / positive regulation of mucus secretion / epidermal growth factor binding / response to UV-A / PLCG1 events in ERBB2 signaling / midgut development / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / hydrogen peroxide metabolic process / ERBB2-EGFR signaling pathway / PTK6 promotes HIF1A stabilization / digestive tract morphogenesis / morphogenesis of an epithelial fold / ERBB2 Activates PTK6 Signaling / intracellular vesicle / Signaling by EGFR / transmembrane receptor protein tyrosine kinase activator activity / protein tyrosine kinase activator activity / negative regulation of epidermal growth factor receptor signaling pathway / response to cobalamin / Signaling by ERBB4 / 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 / MAP kinase kinase kinase activity / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / embryonic placenta development / positive regulation of bone resorption / GAB1 signalosome / positive regulation of G1/S transition of mitotic cell cycle / salivary gland morphogenesis / peptidyl-tyrosine autophosphorylation / positive regulation of phosphorylation / regulation of peptidyl-tyrosine phosphorylation / positive regulation of glial cell proliferation / positive regulation of vasoconstriction / Signaling by ERBB2 / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / cellular response to epidermal growth factor stimulus / EGFR Transactivation by Gastrin / transmembrane receptor protein tyrosine kinase activity / cellular response to cadmium ion / GRB2 events in ERBB2 signaling / positive regulation of DNA repair / neurogenesis / SHC1 events in ERBB2 signaling / regulation of ERK1 and ERK2 cascade / cellular response to dexamethasone stimulus / ossification / positive regulation of synaptic transmission, glutamatergic / positive regulation of epithelial cell proliferation / neuron projection morphogenesis / epithelial cell proliferation / basal plasma membrane / positive regulation of superoxide anion generation / positive regulation of DNA replication / Signal transduction by L1 / cellular response to estradiol stimulus / liver regeneration / NOTCH3 Activation and Transmission of Signal to the Nucleus / astrocyte activation / positive regulation of protein localization to plasma membrane / cellular response to amino acid stimulus / lung development / Signaling by ERBB2 TMD/JMD mutants / positive regulation of smooth muscle cell proliferation / EGFR downregulation / positive regulation of MAP kinase activity / clathrin-coated endocytic vesicle membrane / Constitutive Signaling by EGFRvIII / negative regulation of protein catabolic process / Signaling by ERBB2 ECD mutants / receptor protein-tyrosine kinase / epidermal growth factor receptor signaling pathway / Signaling by ERBB2 KD Mutants / kinase binding / peptidyl-tyrosine phosphorylation / Downregulation of ERBB2 signaling / cell-cell adhesion / positive regulation of miRNA transcription / ruffle 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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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-81C / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.999 Å
AuthorsYan, X.E. / Yun, C.H.
CitationJournal: To Be Published
Title: Crystal structure of EGFR 696-1022 T790M in complex with JTS-1-39
Authors: Yan, X.E. / Yun, C.H.
History
DepositionAug 24, 2016Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 6, 2017Provider: repository / Type: Initial release
Revision 1.1Nov 8, 2023Group: Advisory / Data collection ...Advisory / 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 / pdbx_unobs_or_zero_occ_atoms
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)38,69011
Polymers37,6511
Non-polymers1,04010
Water90150
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1160 Å2
ΔGint-29 kcal/mol
Surface area15300 Å2
Unit cell
Length a, b, c (Å)146.177, 146.177, 146.177
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-1249-

HOH

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Components

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


Mass: 37650.598 Da / Num. of mol.: 1 / Fragment: UNP RESIDUES 696-1022
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-81C / N-[5-[[5-chloranyl-4-[(2-propan-2-ylsulfonylphenyl)amino]pyrimidin-2-yl]amino]-2-(4-ethylpiperazin-1-yl)-4-methoxy-phenyl]prop-2-enamide


Mass: 614.159 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H36ClN7O4S
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Cl
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 50 / Source method: isolated from a natural source / Formula: H2O

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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: 3.45 Å3/Da / Density % sol: 64.34 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 150 mM KCl, 0.1 M HEPES pH 8.0, 38% PEG 300, 50mM Glycyl-glycyl-glycine, 10 mM Co-enzyme A (pH 8.0), 2 mM TCEP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U / Wavelength: 0.97915 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: May 2, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97915 Å / Relative weight: 1
ReflectionResolution: 3→50 Å / Num. obs: 10581 / % possible obs: 100 % / Redundancy: 22 % / Net I/σ(I): 17.56
Reflection shellResolution: 3→3.19 Å

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Processing

Software
NameVersionClassification
PHENIX(dev_2400)refinement
DENZOdata reduction
HKL-3000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2JIT

2jit


Resolution: 2.999→42.198 Å / SU ML: 0.36 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 23.98 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2302 505 4.77 %
Rwork0.1887 --
obs0.1908 10578 99.97 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.999→42.198 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2527 0 63 50 2640
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0092648
X-RAY DIFFRACTIONf_angle_d1.2453580
X-RAY DIFFRACTIONf_dihedral_angle_d27.0351042
X-RAY DIFFRACTIONf_chiral_restr0.067396
X-RAY DIFFRACTIONf_plane_restr0.009448
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.9989-3.30050.31761200.24082488X-RAY DIFFRACTION100
3.3005-3.77790.25481270.20132475X-RAY DIFFRACTION100
3.7779-4.75870.19551270.16472528X-RAY DIFFRACTION100
4.7587-42.20180.22141310.18462582X-RAY DIFFRACTION100

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