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- PDB-5edp: EGFR kinase (T790M/L858R) apo -

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Basic information

Entry
Database: PDB / ID: 5edp
TitleEGFR kinase (T790M/L858R) apo
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / protein kinase / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


response to hydroxyisoflavone / multivesicular body, internal vesicle lumen / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / positive regulation of protein kinase C activity / 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 prolactin secretion / negative regulation of cardiocyte differentiation / positive regulation of protein kinase C activity / 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 / response to UV-A / epidermal growth factor binding / PLCG1 events in ERBB2 signaling / tongue development / midgut development / ERBB2-EGFR signaling pathway / hydrogen peroxide metabolic process / PTK6 promotes HIF1A stabilization / digestive tract morphogenesis / regulation of nitric-oxide synthase activity / morphogenesis of an epithelial fold / ERBB2 Activates PTK6 Signaling / intracellular vesicle / Signaling by EGFR / response to cobalamin / negative regulation of epidermal growth factor receptor signaling pathway / transmembrane receptor protein tyrosine kinase activator activity / protein tyrosine kinase activator activity / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / Signaling by ERBB4 / protein insertion into membrane / eyelid development in camera-type eye / cerebral cortex cell migration / ERBB2 Regulates Cell Motility / regulation of JNK cascade / activation of phospholipase C activity / PI3K events in ERBB2 signaling / positive regulation of cyclin-dependent protein serine/threonine kinase activity / negative regulation of mitotic cell cycle / hair follicle development / MAP kinase kinase kinase activity / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / positive regulation of G1/S transition of mitotic cell cycle / embryonic placenta development / positive regulation of DNA replication / positive regulation of bone resorption / GAB1 signalosome / positive regulation of nitric oxide mediated signal transduction / salivary gland morphogenesis / regulation of peptidyl-tyrosine phosphorylation / peptidyl-tyrosine autophosphorylation / positive regulation of vasoconstriction / positive regulation of glial cell proliferation / positive regulation of phosphorylation / Signaling by ERBB2 / cellular response to epidermal growth factor stimulus / cellular response to cadmium ion / positive regulation of DNA repair / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / GRB2 events in ERBB2 signaling / neurogenesis / transmembrane receptor protein tyrosine kinase activity / ossification / cellular response to dexamethasone stimulus / SHC1 events in ERBB2 signaling / positive regulation of synaptic transmission, glutamatergic / basal plasma membrane / regulation of ERK1 and ERK2 cascade / neuron projection morphogenesis / positive regulation of superoxide anion generation / Signal transduction by L1 / epithelial cell proliferation / cellular response to estradiol stimulus / liver regeneration / NOTCH3 Activation and Transmission of Signal to the Nucleus / positive regulation of epithelial cell proliferation / astrocyte activation / cellular response to amino acid stimulus / positive regulation of protein localization to plasma membrane / EGFR downregulation / clathrin-coated endocytic vesicle membrane / lung development / positive regulation of smooth muscle cell proliferation / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII / positive regulation of MAP kinase activity / Signaling by ERBB2 ECD mutants / epidermal growth factor receptor signaling pathway / Signaling by ERBB2 KD Mutants / negative regulation of protein catabolic process / cell-cell adhesion / receptor protein-tyrosine kinase / ruffle membrane / Downregulation of ERBB2 signaling / kinase binding
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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / 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
Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.9 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

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Assembly

Deposited unit
A: Epidermal growth factor receptor


Theoretical massNumber of molelcules
Total (without water)37,5491
Polymers37,5491
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area15610 Å2
MethodPISA
Unit cell
Length a, b, c (Å)148.847, 148.847, 148.847
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

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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: 66.39 %
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: CLSI / Beamline: 08B1-1 / Wavelength: 1.0332 Å
DetectorType: RAYONIX MX300HE / Detector: CCD / Date: Feb 11, 2012
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 2.9→47.1 Å / Num. all: 12322 / Num. obs: 12322 / % possible obs: 100 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 11.3 % / Biso Wilson estimate: 82.93 Å2 / Rsym value: 0.106 / Net I/σ(I): 23.8

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Processing

Software
NameVersionClassification
BUSTER2.11.5refinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing
RefinementResolution: 2.9→47.07 Å / Cor.coef. Fo:Fc: 0.9326 / Cor.coef. Fo:Fc free: 0.8942 / SU R Cruickshank DPI: 0.526 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.492 / SU Rfree Blow DPI: 0.3 / SU Rfree Cruickshank DPI: 0.309
RfactorNum. reflection% reflectionSelection details
Rfree0.2441 530 4.3 %RANDOM
Rwork0.1998 ---
obs0.2016 12322 99.85 %-
Displacement parametersBiso mean: 75.62 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refine analyzeLuzzati coordinate error obs: 0.461 Å
Refinement stepCycle: 1 / Resolution: 2.9→47.07 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2366 0 0 0 2366
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0092417HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.073271HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d853SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes56HARMONIC2
X-RAY DIFFRACTIONt_gen_planes338HARMONIC5
X-RAY DIFFRACTIONt_it2417HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.6
X-RAY DIFFRACTIONt_other_torsion19.19
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion317SEMIHARMONIC5
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_contact2735SEMIHARMONIC4
LS refinement shellResolution: 2.9→3.18 Å / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.2947 118 4.06 %
Rwork0.2334 2788 -
all0.2358 2906 -
obs--99.85 %
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)
11.32340.9419-0.64490.14510.485.68910.0203-0.03030.0099-0.09780.0387-0.0920.00940.5442-0.0591-0.0381-0.12080.0824-0.05510.0562-0.0082-54.15647.0793-33.1172
22.37961.9055-1.01985.2411-1.51642.4517-0.1521-0.3269-0.38-0.5426-0.2215-0.54420.29610.39190.3736-0.0716-0.03210.126-0.09030.1407-0.1501-62.0731-15.9842-23.1118
35.024-1.74060.56694.15212.20910.8310.0079-0.07920.03390.1166-0.00560.0006-0.0764-0.0863-0.00230.0321-0.1520.1072-0.0173-0.152-0.0095-66.58189.1402-17.8565
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{A|696 - A|786}
2X-RAY DIFFRACTION2{A|787 - A|987 Z|1 - Z|1}
3X-RAY DIFFRACTION3{A|988 - A|1020}

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