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- PDB-6jrx: EGFR T790M/C797S in complex with compound 6i -

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Basic information

Entry
Database: PDB / ID: 6jrx
TitleEGFR T790M/C797S in complex with compound 6i
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / EGFR T790M/C797S / 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 / response to UV-A / tongue development / PLCG1 events in ERBB2 signaling / midgut development / ERBB2-EGFR signaling pathway / digestive tract morphogenesis / hydrogen peroxide metabolic process / PTK6 promotes HIF1A stabilization / morphogenesis of an epithelial fold / 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 / positive regulation of cyclin-dependent protein serine/threonine kinase activity / Signaling by ERBB4 / protein tyrosine kinase activator activity / Respiratory syncytial virus (RSV) attachment and entry / regulation of peptidyl-tyrosine phosphorylation / 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 / embryonic placenta development / positive regulation of bone resorption / positive regulation of phosphorylation / salivary gland morphogenesis / peptidyl-tyrosine autophosphorylation / 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 / histone H3Y41 kinase activity / histone H2AXY142 kinase activity / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / GRB2 events in ERBB2 signaling / cellular response to epidermal growth factor stimulus / SHC1 events in ERBB2 signaling / cellular response to dexamethasone stimulus / positive regulation of synaptic transmission, glutamatergic / ossification / positive regulation of DNA repair / positive regulation of peptidyl-serine phosphorylation / neuron projection morphogenesis / positive regulation of superoxide anion generation / positive regulation of epithelial cell proliferation / basal plasma membrane / liver regeneration / epithelial cell proliferation / Signal transduction by L1 / neurogenesis / positive regulation of DNA replication / positive regulation of protein localization to plasma membrane / astrocyte activation / 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 / cell surface receptor protein tyrosine kinase signaling pathway / 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
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-9JO / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.201 Å
AuthorsZhu, S.J. / Yun, C.H.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Design, Synthesis, and Structure-Activity Relationships of 1,2,3-Triazole Benzenesulfonamides as New Selective Leucine-Zipper and Sterile-alpha Motif Kinase (ZAK) Inhibitors.
Authors: Yang, J. / Shibu, M.A. / Kong, L. / Luo, J. / BadrealamKhan, F. / Huang, Y. / Tu, Z.C. / Yun, C.H. / Huang, C.Y. / Ding, K. / Lu, X.
History
DepositionApr 6, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 15, 2020Provider: repository / Type: Initial release
Revision 1.1Mar 27, 2024Group: Advisory / Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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)38,2522
Polymers37,6351
Non-polymers6171
Water1,15364
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area14750 Å2
Unit cell
Length a, b, c (Å)144.824, 144.824, 144.824
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: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 64 / 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: 3.38 Å3/Da / Density % sol: 63.59 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop
Details: 0.1 M HEPES pH8.5, 40% PEG400, 0.15 M NaCl, 5 mM tris(2-carboxyethyl)-phosphine (TCEP)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.97853 Å
DetectorType: DECTRIS PILATUS 300K / Detector: PIXEL / Date: Jan 7, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97853 Å / Relative weight: 1
ReflectionResolution: 2.2→50 Å / Num. obs: 25643 / % possible obs: 100 % / Redundancy: 20 % / Net I/σ(I): 37.5
Reflection shellResolution: 2.2→2.3 Å

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Processing

Software
NameVersionClassification
PHENIX(1.12_2829: ???)refinement
HKL-3000data reduction
HKL-3000data scaling
PHENIXphasing
RefinementResolution: 2.201→24.137 Å / SU ML: 0.27 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 25.64
RfactorNum. reflection% reflection
Rfree0.2392 1306 5.09 %
Rwork0.2094 --
obs0.211 25643 99.82 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.201→24.137 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2390 0 44 64 2498
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0092489
X-RAY DIFFRACTIONf_angle_d1.0643369
X-RAY DIFFRACTIONf_dihedral_angle_d21.8871497
X-RAY DIFFRACTIONf_chiral_restr0.061372
X-RAY DIFFRACTIONf_plane_restr0.006419
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2014-2.28950.29311440.27392692X-RAY DIFFRACTION100
2.2895-2.39360.30171340.25822671X-RAY DIFFRACTION100
2.3936-2.51960.30321570.25542673X-RAY DIFFRACTION100
2.5196-2.67730.27411360.24622693X-RAY DIFFRACTION100
2.6773-2.88370.28231350.23972699X-RAY DIFFRACTION100
2.8837-3.17330.2761430.2362716X-RAY DIFFRACTION100
3.1733-3.63120.23291540.21512702X-RAY DIFFRACTION100
3.6312-4.56980.21541530.17932719X-RAY DIFFRACTION100
4.5698-24.13880.21031500.18612772X-RAY DIFFRACTION99

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