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- PDB-4rj4: EGFR kinase (T790M/L858R) with inhibitor compound 6 -

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Basic information

Entry
Database: PDB / ID: 4rj4
TitleEGFR kinase (T790M/L858R) with inhibitor compound 6
ComponentsEpidermal growth factor receptor
KeywordsTransferase/transferase inhibitor / protein kinase / phosphotransfer catalyst / Transferase-transferase inhibitor complex
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 / EGFR interacts with phospholipase C-gamma / epidermal growth factor receptor activity / 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 / EGFR interacts with phospholipase C-gamma / epidermal growth factor receptor activity / regulation of peptidyl-tyrosine phosphorylation / epidermal growth factor binding / response to UV-A / PLCG1 events in ERBB2 signaling / ERBB2-EGFR signaling pathway / morphogenesis of an epithelial fold / PTK6 promotes HIF1A stabilization / ERBB2 Activates PTK6 Signaling / digestive tract morphogenesis / Signaling by EGFR / intracellular vesicle / eyelid development in camera-type eye / negative regulation of epidermal growth factor receptor signaling pathway / cerebral cortex cell migration / protein insertion into membrane / ERBB2 Regulates Cell Motility / protein tyrosine kinase activator activity / Respiratory syncytial virus (RSV) attachment and entry / Signaling by ERBB4 / PI3K events in ERBB2 signaling / positive regulation of phosphorylation / positive regulation of peptidyl-serine phosphorylation / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / hair follicle development / MAP kinase kinase kinase activity / GAB1 signalosome / positive regulation of G1/S transition of mitotic cell cycle / embryonic placenta development / salivary gland morphogenesis / Signaling by ERBB2 / GRB2 events in EGFR signaling / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / SHC1 events in EGFR signaling / transmembrane receptor protein tyrosine kinase activity / EGFR Transactivation by Gastrin / GRB2 events in ERBB2 signaling / SHC1 events in ERBB2 signaling / ossification / NOTCH3 Activation and Transmission of Signal to the Nucleus / positive regulation of DNA repair / basal plasma membrane / cellular response to epidermal growth factor stimulus / EGFR downregulation / positive regulation of DNA replication / epithelial cell proliferation / Signal transduction by L1 / positive regulation of epithelial cell proliferation / positive regulation of protein localization to plasma membrane / cellular response to amino acid stimulus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / cellular response to estradiol stimulus / clathrin-coated endocytic vesicle membrane / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII / Downregulation of ERBB2 signaling / cell-cell adhesion / receptor protein-tyrosine kinase / negative regulation of protein catabolic process / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / positive regulation of miRNA transcription / kinase binding / ruffle membrane / positive regulation of protein phosphorylation / epidermal growth factor receptor signaling pathway / neuron differentiation / cell morphogenesis / positive regulation of fibroblast proliferation / HCMV Early Events / Constitutive Signaling by Aberrant PI3K in Cancer / actin filament binding / Cargo recognition for clathrin-mediated endocytosis / cell junction / transmembrane signaling receptor activity / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / positive regulation of canonical Wnt signaling pathway / Clathrin-mediated endocytosis / PIP3 activates AKT signaling / virus receptor activity / ATPase binding / RAF/MAP kinase cascade / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / positive regulation of cell growth / double-stranded DNA binding / protein tyrosine kinase activity / early endosome membrane / protein phosphatase binding / nuclear membrane / basolateral plasma membrane / learning or memory / Extra-nuclear estrogen signaling / cell surface receptor signaling pathway / 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 / 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-3QW / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.78 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)37,9822
Polymers37,5491
Non-polymers4331
Water543
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)146.559, 146.559, 146.559
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 / 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-3QW / N-[2-(4-methoxypiperidin-1-yl)pyrimidin-4-yl]-1-(propan-2-yl)-2-(1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridin-6-amine


Mass: 432.521 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H28N8O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 3 / 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: 3.49 Å3/Da / Density % sol: 64.79 %
Crystal growTemperature: 292 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: PEG 10,000, ethyene 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: 5.0.1 / Wavelength: 0.977408 Å
DetectorType: ADSC QUANTUM 210r / Detector: CCD / Date: May 2, 2012
RadiationMonochromator: Si(220) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.977408 Å / Relative weight: 1
ReflectionResolution: 2.78→59.83 Å / Num. all: 13292 / Num. obs: 13291 / % possible obs: 100 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 8.8 % / Biso Wilson estimate: 74.46 Å2 / Rsym value: 0.07 / Net I/σ(I): 28.1

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Processing

Software
NameVersionClassification
B3data collection
PHASERphasing
BUSTER2.11.4refinement
XDSdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 1M17

1m17


Resolution: 2.78→50 Å / Cor.coef. Fo:Fc: 0.936 / Cor.coef. Fo:Fc free: 0.911 / SU R Cruickshank DPI: 0.433 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2255 570 4.29 %RANDOM
Rwork0.1882 ---
obs0.1898 13291 99.53 %-
all-13292 --
Displacement parametersBiso mean: 58.52 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refine analyzeLuzzati coordinate error obs: 0.366 Å
Refinement stepCycle: LAST / Resolution: 2.78→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2403 0 32 3 2438
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0092491HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.13373HARMONIC2
X-RAY DIFFRACTIONo_angle_deg1873SINUSOIDAL2
X-RAY DIFFRACTIONc_angle_d158HARMONIC2
X-RAY DIFFRACTIONt_gen_planes0347HARMONIC5
X-RAY DIFFRACTIONt_it02491HARMONIC20
X-RAY DIFFRACTIONt_omega_torsion2.79
X-RAY DIFFRACTIONt_other_torsion19.31
X-RAY DIFFRACTIONt_chiral_improper_torsion0321SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact02778SEMIHARMONIC4
LS refinement shellResolution: 2.78→3 Å / Total num. of bins used: 7
RfactorNum. reflection% reflection
Rfree0.2456 106 3.99 %
Rwork0.2034 2551 -
all0.2051 2657 -
obs--99.53 %
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)
10.84670.3967-0.5630.26980.54584.2873-0.0126-0.1508-0.0234-0.05940.0096-0.1241-0.18120.54420.00290.0228-0.08030.0722-0.01630.0186-0.0223-54.86387.9136-30.3821
21.32890.8963-0.38063.1944-1.00681.5062-0.1069-0.1359-0.2372-0.3903-0.1494-0.43740.23080.2380.2563-0.03960.02740.1078-0.05540.0641-0.0879-61.0519-15.7194-22.1485
31.1156-1.3967-0.76380.29380.08570.3786-0.0072-0.06190.01960.04310.00190.0094-0.0056-0.01990.00530.0597-0.088-0.01260.09730.0867-0.0481-65.03364.4707-7.4326
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|697 - A|786 A|1005 - A|1018 }A697 - 786
2X-RAY DIFFRACTION1{ A|697 - A|786 A|1005 - A|1018 }A1005 - 1018
3X-RAY DIFFRACTION2{ A|787 - A|987 A|1101 - A|1101 }A787 - 987
4X-RAY DIFFRACTION2{ A|787 - A|987 A|1101 - A|1101 }A1101
5X-RAY DIFFRACTION3{ A|988 - A|998 }A988 - 998

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