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- PDB-5zto: Crystal structure of EGFR 696-1022 T790M/C797S in complex with D3003 -

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Basic information

Entry
Database: PDB / ID: 5zto
TitleCrystal structure of EGFR 696-1022 T790M/C797S in complex with D3003
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / EGFR / T790M/C797S / 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 / Inhibition of Signaling by Overexpressed EGFR / epidermal growth factor receptor activity ...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 / 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 / tongue development / PLCG1 events in ERBB2 signaling / midgut development / hydrogen peroxide metabolic process / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / 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 / negative regulation of epidermal growth factor receptor signaling pathway / response to cobalamin / Signaling by ERBB4 / protein tyrosine kinase activator activity / eyelid development in camera-type eye / protein insertion into membrane / cerebral cortex cell migration / ERBB2 Regulates Cell Motility / regulation of JNK cascade / Respiratory syncytial virus (RSV) attachment and entry / PI3K events in ERBB2 signaling / positive regulation of cyclin-dependent protein serine/threonine kinase activity / negative regulation of mitotic cell cycle / MAP kinase kinase kinase activity / hair follicle development / 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 / Signaling by ERBB2 / positive regulation of vasoconstriction / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / cellular response to epidermal growth factor stimulus / cellular response to cadmium ion / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / GRB2 events in ERBB2 signaling / transmembrane receptor protein tyrosine kinase activity / positive regulation of DNA repair / SHC1 events in ERBB2 signaling / cellular response to dexamethasone stimulus / ossification / regulation of ERK1 and ERK2 cascade / positive regulation of synaptic transmission, glutamatergic / basal plasma membrane / neuron projection morphogenesis / neurogenesis / positive regulation of epithelial cell proliferation / positive regulation of superoxide anion generation / positive regulation of DNA replication / epithelial cell proliferation / Signal transduction by L1 / cellular response to estradiol stimulus / astrocyte activation / NOTCH3 Activation and Transmission of Signal to the Nucleus / liver regeneration / positive regulation of protein localization to plasma membrane / Signaling by ERBB2 TMD/JMD mutants / cellular response to amino acid stimulus / positive regulation of smooth muscle cell proliferation / EGFR downregulation / lung development / positive regulation of MAP kinase activity / Constitutive Signaling by EGFRvIII / clathrin-coated endocytic vesicle membrane / Signaling by ERBB2 ECD mutants / epidermal growth factor receptor signaling pathway / Signaling by ERBB2 KD Mutants / negative regulation of protein catabolic process / receptor protein-tyrosine kinase / kinase binding / positive regulation of miRNA transcription / Downregulation of ERBB2 signaling / cell-cell adhesion / ruffle membrane / HCMV Early Events
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-9JO / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.649 Å
AuthorsZhu, S.J. / Yun, C.H.
CitationJournal: To Be Published
Title: Crystal structure of EGFR 696-1022 T790M/C797S in complex with D3003
Authors: Zhu, S.J. / Yun, C.H.
History
DepositionMay 4, 2018Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 12, 2019Provider: repository / Type: Initial release
Revision 1.1Nov 22, 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

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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)38,2873
Polymers37,6351
Non-polymers6532
Water68538
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area130 Å2
ΔGint-10 kcal/mol
Surface area14580 Å2
Unit cell
Length a, b, c (Å)148.731, 148.731, 148.731
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: 37634.535 Da / Num. of mol.: 1 / Mutation: T790M, C797S
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-9JO / N-{trans-4-[3-(2-chlorophenyl)-7-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl]cyclohexyl}propanamide


Mass: 617.184 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C33H41ClN8O2
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 38 / 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: 3.64 Å3/Da / Density % sol: 66.23 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 8 / Details: 0.05M HEPES pH 8.0, 0.2M ZnSO4, 25% PEG 600

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.97774 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Jun 19, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97774 Å / Relative weight: 1
ReflectionResolution: 2.649→50 Å / Num. obs: 16088 / % possible obs: 100 % / Redundancy: 18 % / Rmerge(I) obs: 0.127 / Net I/σ(I): 6
Reflection shellResolution: 2.649→2.71 Å / Rmerge(I) obs: 0.353

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Processing

Software
NameVersionClassification
PHENIX(1.12_2829: ???)refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2itv

2itv


Resolution: 2.649→47.033 Å / SU ML: 0.4 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 30.32
RfactorNum. reflection% reflection
Rfree0.2724 805 5.01 %
Rwork0.2314 --
obs0.2335 16080 99.95 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.649→47.033 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2268 0 45 38 2351
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0112376
X-RAY DIFFRACTIONf_angle_d1.123238
X-RAY DIFFRACTIONf_dihedral_angle_d23.828898
X-RAY DIFFRACTIONf_chiral_restr0.388370
X-RAY DIFFRACTIONf_plane_restr0.007407
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.6492-2.81510.38351470.30562506X-RAY DIFFRACTION100
2.8151-3.03240.35811230.30532542X-RAY DIFFRACTION100
3.0324-3.33750.28691260.27952540X-RAY DIFFRACTION100
3.3375-3.82030.35251330.24242510X-RAY DIFFRACTION100
3.8203-4.81240.2191090.20132576X-RAY DIFFRACTION100
4.8124-47.04030.23991670.20562601X-RAY DIFFRACTION100

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