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- PDB-4rj7: EGFR kinase (T790M/L858R) with inhibitor compound 1 -

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Basic information

Entry
Database: PDB / ID: 4rj7
TitleEGFR kinase (T790M/L858R) with inhibitor compound 1
ComponentsEpidermal growth factor receptor
KeywordsTransferase/Transferase inhibitor / protein kinase / phosphotransfer catalyst / Transferase-Transferase inhibitor complex
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-3R1 / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.55 Å
AuthorsEigenbrot, C. / Yu, C.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Discovery of Selective and Noncovalent Diaminopyrimidine-Based Inhibitors of Epidermal Growth Factor Receptor Containing the T790M Resistance Mutation.
Authors: Hanan, E.J. / Eigenbrot, C. / Bryan, M.C. / Burdick, D.J. / Chan, B.K. / Chen, Y. / Dotson, J. / Heald, R.A. / Jackson, P.S. / La, H. / Lainchbury, M.D. / Malek, S. / Purkey, H.E. / ...Authors: Hanan, E.J. / Eigenbrot, C. / Bryan, M.C. / Burdick, D.J. / Chan, B.K. / Chen, Y. / Dotson, J. / Heald, R.A. / Jackson, P.S. / La, H. / Lainchbury, M.D. / Malek, S. / Purkey, H.E. / Schaefer, G. / Schmidt, S. / Seward, E.M. / Sideris, S. / Tam, C. / Wang, S. / Yeap, S.K. / Yen, I. / Yin, J. / Yu, C. / Zilberleyb, I. / Heffron, T.P.
History
DepositionOct 8, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 26, 2014Provider: repository / Type: Initial release
Revision 1.1Dec 10, 2014Group: Database references
Revision 1.2Jan 14, 2015Group: Database references
Revision 1.3Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)38,0933
Polymers37,5491
Non-polymers5432
Water50428
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)146.605, 146.605, 146.605
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: 37549.398 Da / Num. of mol.: 1 / Fragment: kinase domain (UNP residues 695-1022) / Mutation: T790M, L858R, E865A, E866A, K867A
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-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-3R1 / 2,6-dichloro-N-{2-[(2-{[(2S)-1-hydroxypropan-2-yl]amino}-6-methylpyrimidin-4-yl)amino]pyridin-4-yl}benzamide


Mass: 447.318 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H20Cl2N6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 28 / 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: 3.5 Å3/Da / Density % sol: 64.82 %
Crystal growTemperature: 292 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: PEG 10,000, ethylene glycol, pH 7.5, VAPOR DIFFUSION, SITTING DROP, temperature 292K

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1.00003 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Nov 6, 2013
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00003 Å / Relative weight: 1
ReflectionResolution: 2.55→50 Å / Num. all: 17144 / Num. obs: 17143 / % possible obs: 100 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 5.9 % / Biso Wilson estimate: 67.43 Å2 / Rsym value: 0.066 / Net I/σ(I): 22.2

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Processing

Software
NameVersionClassification
B3data collection
PHASERphasing
BUSTER2.11.4refinement
HKL-2000data reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 1M17

1m17


Resolution: 2.55→46.36 Å / Cor.coef. Fo:Fc: 0.9426 / Cor.coef. Fo:Fc free: 0.9335 / SU R Cruickshank DPI: 0.306 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2335 713 4.16 %RANDOM
Rwork0.2059 ---
obs0.207 17143 99.41 %-
all-17144 --
Displacement parametersBiso mean: 63.83 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refine analyzeLuzzati coordinate error obs: 0.389 Å
Refinement stepCycle: LAST / Resolution: 2.55→46.36 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2370 0 35 28 2433
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012500HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.113382HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d0884SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes057HARMONIC2
X-RAY DIFFRACTIONt_gen_planes0348HARMONIC5
X-RAY DIFFRACTIONt_it02500HARMONIC20
X-RAY DIFFRACTIONt_omega_torsion3.04
X-RAY DIFFRACTIONt_other_torsion18.95
X-RAY DIFFRACTIONt_chiral_improper_torsion0323SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact02857SEMIHARMONIC4
LS refinement shellResolution: 2.55→2.71 Å / Total num. of bins used: 9
RfactorNum. reflection% reflection
Rfree0.3329 103 3.76 %
Rwork0.2392 2634 -
all0.2423 2737 -
obs--99.41 %
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)
10.67570.3527-0.51660.41610.55655.32290.0222-0.04950.10210.01530.0281-0.1249-0.29590.5442-0.0503-0.0153-0.11930.0275-0.0440.0251-0.068-54.94428.0421-29.9466
21.52410.9084-0.3513.6803-0.65711.3783-0.1171-0.1126-0.2026-0.3137-0.0789-0.50910.1740.23430.196-0.047-0.0060.102-0.08680.0436-0.1277-61.0269-15.6778-22.0131
30.7819-1.189-0.64350.33940.32440.8365-0.0074-0.05130.02560.0360.00640.0227-0.0178-0.01290.0010.0502-0.11770.03610.04030.152-0.0155-65.02224.2231-7.5174
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|697 - A|786 A|1006 - A|1018 }A697 - 786
2X-RAY DIFFRACTION1{ A|697 - A|786 A|1006 - A|1018 }A1006 - 1018
3X-RAY DIFFRACTION2{ A|787 - A|987 A|1102 - A|1102 }A787 - 987
4X-RAY DIFFRACTION2{ A|787 - A|987 A|1102 - A|1102 }A1102
5X-RAY DIFFRACTION3{ A|988 - A|997 }A988 - 997

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