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- PDB-5edr: EGFR kinase (T790M/L858R) with inhibitor compound 27: ~{N}-(1~{H}... -

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Basic information

Entry
Database: PDB / ID: 5edr
TitleEGFR kinase (T790M/L858R) with inhibitor compound 27: ~{N}-(1~{H}-indazol-3-yl)-7,7-dimethyl-2-(2-methylpyrazol-3-yl)-5~{H}-furo[3,4-d]pyrimidin-4-amine
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / protein kinase / inhibitor / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


positive regulation of protein kinase C activity / multivesicular body, internal vesicle lumen / negative regulation of cardiocyte differentiation / response to hydroxyisoflavone / diterpenoid metabolic process / positive regulation of prolactin secretion / 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 / negative regulation of cardiocyte differentiation / response to hydroxyisoflavone / diterpenoid metabolic process / positive regulation of prolactin secretion / Shc-EGFR complex / Inhibition of Signaling by Overexpressed EGFR / ovulation cycle / EGFR interacts with phospholipase C-gamma / positive regulation of mucus secretion / regulation of peptidyl-tyrosine phosphorylation / epidermal growth factor binding / tongue development / response to UV-A / PLCG1 events in ERBB2 signaling / midgut development / ERBB2-EGFR signaling pathway / hydrogen peroxide metabolic process / morphogenesis of an epithelial fold / PTK6 promotes HIF1A stabilization / ERBB2 Activates PTK6 Signaling / digestive tract morphogenesis / Signaling by EGFR / response to cobalamin / intracellular vesicle / 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 / protein tyrosine kinase activator activity / Respiratory syncytial virus (RSV) attachment and entry / positive regulation of bone resorption / Signaling by ERBB4 / PI3K events in ERBB2 signaling / negative regulation of mitotic cell cycle / positive regulation of phosphorylation / placental growth factor receptor activity / hepatocyte growth factor receptor activity / boss receptor activity / stem cell factor receptor activity / platelet-derived growth factor beta-receptor activity / brain-derived neurotrophic factor receptor activity / positive regulation of peptidyl-serine phosphorylation / platelet-derived growth factor alpha-receptor activity / epidermal growth factor receptor activity / hair follicle development / macrophage colony-stimulating factor receptor activity / peptidyl-tyrosine autophosphorylation / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / protein tyrosine kinase collagen receptor activity / MAP kinase kinase kinase activity / positive regulation of G1/S transition of mitotic cell cycle / GAB1 signalosome / transmembrane-ephrin receptor activity / insulin-like growth factor receptor activity / embryonic placenta development / vascular endothelial growth factor receptor activity / GPI-linked ephrin receptor activity / salivary gland morphogenesis / positive regulation of vasoconstriction / fibroblast growth factor receptor activity / insulin receptor activity / Signaling by ERBB2 / positive regulation of glial cell proliferation / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / transmembrane receptor protein tyrosine kinase activity / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / cellular response to dexamethasone stimulus / GRB2 events in ERBB2 signaling / positive regulation of synaptic transmission, glutamatergic / SHC1 events in ERBB2 signaling / ossification / basal plasma membrane / positive regulation of DNA repair / cellular response to epidermal growth factor stimulus / positive regulation of epithelial cell proliferation / positive regulation of superoxide anion generation / positive regulation of DNA replication / epithelial cell proliferation / neuron projection morphogenesis / Signal transduction by L1 / positive regulation of smooth muscle cell proliferation / positive regulation of protein localization to plasma membrane / astrocyte activation / liver regeneration / cellular response to amino acid stimulus / NOTCH3 Activation and Transmission of Signal to the Nucleus / cellular response to estradiol stimulus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / lung development / EGFR downregulation / synaptic membrane / clathrin-coated endocytic vesicle membrane / peptidyl-tyrosine phosphorylation / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII
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-5N4 / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.6 Å
AuthorsEigenbrot, C. / Yu, C.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2016
Title: 4-Aminoindazolyl-dihydrofuro[3,4-d]pyrimidines as non-covalent inhibitors of mutant epidermal growth factor receptor tyrosine kinase.
Authors: Hanan, E.J. / Baumgardner, M. / Bryan, M.C. / Chen, Y. / Eigenbrot, C. / Fan, P. / Gu, X.H. / La, H. / Malek, S. / Purkey, H.E. / Schaefer, G. / Schmidt, S. / Sideris, S. / Yen, I. / Yu, C. / Heffron, T.P.
History
DepositionOct 21, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 2, 2015Provider: repository / Type: Initial release
Revision 1.1Dec 23, 2015Group: Database references
Revision 1.2Jan 20, 2016Group: Database references
Revision 1.3Mar 6, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / database_2 / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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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)37,9112
Polymers37,5491
Non-polymers3611
Water1,02757
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area15620 Å2
MethodPISA
Unit cell
Length a, b, c (Å)148.800, 148.800, 148.800
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-5N4 / ~{N}-(1~{H}-indazol-3-yl)-7,7-dimethyl-2-(2-methylpyrazol-3-yl)-5~{H}-furo[3,4-d]pyrimidin-4-amine


Mass: 361.400 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H19N7O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 57 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 3.66 Å3/Da / Density % sol: 66.36 %
Crystal growTemperature: 292 K / Method: vapor diffusion, sitting drop / pH: 7.5 / Details: PEG 10K, ethylene glycol

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 29, 2012
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.6→47 Å / Num. all: 16882 / Num. obs: 16882 / % possible obs: 99.1 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 3.9 % / Biso Wilson estimate: 78.88 Å2 / Rsym value: 0.056 / Net I/σ(I): 23

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Processing

Software
NameVersionClassification
BUSTER2.11.5refinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing
RefinementResolution: 2.6→47 Å / Cor.coef. Fo:Fc: 0.9438 / Cor.coef. Fo:Fc free: 0.9311 / SU R Cruickshank DPI: 0.298 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.292 / SU Rfree Blow DPI: 0.211 / SU Rfree Cruickshank DPI: 0.215
RfactorNum. reflection% reflectionSelection details
Rfree0.2151 701 4.16 %RANDOM
Rwork0.1906 ---
obs0.1916 16852 99.07 %-
Displacement parametersBiso mean: 77.17 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refine analyzeLuzzati coordinate error obs: 0.427 Å
Refinement stepCycle: 1 / Resolution: 2.6→47 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2409 0 27 57 2493
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012493HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.083381HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d874SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes60HARMONIC2
X-RAY DIFFRACTIONt_gen_planes349HARMONIC5
X-RAY DIFFRACTIONt_it2493HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.93
X-RAY DIFFRACTIONt_other_torsion18.76
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion322SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2845SEMIHARMONIC4
LS refinement shellResolution: 2.6→2.78 Å / Total num. of bins used: 8
RfactorNum. reflection% reflection
Rfree0.2615 115 3.79 %
Rwork0.2229 2917 -
all0.2243 3032 -
obs--99.07 %
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)
12.605-0.6989-0.88590.68090.04416.52160.0672-0.26860.31520.0190.0339-0.3078-0.00850.5442-0.1011-0.05-0.1520.0714-0.03430.0897-0.0388-53.93817.133-32.9599
22.34642.3124-1.31256.5279-2.08372.416-0.245-0.1286-0.2463-0.4906-0.0492-0.54420.32680.25180.2942-0.0495-0.08780.1115-0.09020.1188-0.2166-61.9704-15.7383-23.061
33.1393-0.4953-2.40637.86562.85790.5536-0.0406-0.15910.05740.2486-0.05980.1441-0.0076-0.05920.10050.051-0.1520.0289-0.0584-0.1053-0.0475-65.794810.3318-17.2105
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|697 - A|786 }A697 - 786
2X-RAY DIFFRACTION2{ A|787 - A|987 A|1101 - A|1101 }A787 - 987
3X-RAY DIFFRACTION2{ A|787 - A|987 A|1101 - A|1101 }A1101
4X-RAY DIFFRACTION3{ A|988 - A|1018 }A988 - 1018

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