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- PDB-6s9c: EGFR-KINASE IN COMPLEX WITH COMPOUND 5 -

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Basic information

Entry
Database: PDB / ID: 6s9c
TitleEGFR-KINASE IN COMPLEX WITH COMPOUND 5
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE / EGF RECEPTOR KINASE MUTANT T790M / L858R / Inhibitor
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 / transmembrane receptor protein tyrosine kinase activator activity / protein tyrosine kinase activator activity / negative regulation of epidermal growth factor receptor signaling pathway / Signaling by ERBB4 / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / eyelid development in camera-type eye / protein insertion into membrane / cerebral cortex cell migration / ERBB2 Regulates Cell Motility / regulation of JNK cascade / : / 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 / embryonic placenta development / positive regulation of bone resorption / positive regulation of G1/S transition of mitotic cell cycle / GAB1 signalosome / positive regulation of nitric oxide mediated signal transduction / salivary gland morphogenesis / peptidyl-tyrosine autophosphorylation / regulation of peptidyl-tyrosine phosphorylation / positive regulation of phosphorylation / positive regulation of glial cell proliferation / positive regulation of vasoconstriction / Signaling by ERBB2 / cellular response to epidermal growth factor stimulus / cellular response to cadmium ion / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / positive regulation of DNA repair / EGFR Transactivation by Gastrin / GRB2 events in ERBB2 signaling / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / transmembrane receptor protein tyrosine kinase activity / SHC1 events in ERBB2 signaling / ossification / positive regulation of synaptic transmission, glutamatergic / neurogenesis / cellular response to dexamethasone stimulus / basal plasma membrane / regulation of ERK1 and ERK2 cascade / neuron projection morphogenesis / positive regulation of superoxide anion generation / positive regulation of DNA replication / Signal transduction by L1 / epithelial cell proliferation / cellular response to estradiol stimulus / NOTCH3 Activation and Transmission of Signal to the Nucleus / positive regulation of epithelial cell proliferation / astrocyte activation / liver regeneration / positive regulation of protein localization to plasma membrane / EGFR downregulation / cell surface receptor protein tyrosine kinase signaling pathway / cellular response to amino acid stimulus / positive regulation of smooth muscle cell proliferation / Signaling by ERBB2 TMD/JMD mutants / positive regulation of MAP kinase activity / clathrin-coated endocytic vesicle membrane / lung development / Constitutive Signaling by EGFRvIII / 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 / Downregulation of ERBB2 signaling / kinase binding / ruffle 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 / 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
Chem-L1K / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.73 Å
AuthorsBader, G.
CitationJournal: J.Med.Chem. / Year: 2019
Title: Start Selective and Rigidify: The Discovery Path toward a Next Generation of EGFR Tyrosine Kinase Inhibitors.
Authors: Engelhardt, H. / Bose, D. / Petronczki, M. / Scharn, D. / Bader, G. / Baum, A. / Bergner, A. / Chong, E. / Dobel, S. / Egger, G. / Engelhardt, C. / Ettmayer, P. / Fuchs, J.E. / Gerstberger, ...Authors: Engelhardt, H. / Bose, D. / Petronczki, M. / Scharn, D. / Bader, G. / Baum, A. / Bergner, A. / Chong, E. / Dobel, S. / Egger, G. / Engelhardt, C. / Ettmayer, P. / Fuchs, J.E. / Gerstberger, T. / Gonnella, N. / Grimm, A. / Grondal, E. / Haddad, N. / Hopfgartner, B. / Kousek, R. / Krawiec, M. / Kriz, M. / Lamarre, L. / Leung, J. / Mayer, M. / Patel, N.D. / Simov, B.P. / Reeves, J.T. / Schnitzer, R. / Schrenk, A. / Sharps, B. / Solca, F. / Stadtmuller, H. / Tan, Z. / Wunberg, T. / Zoephel, A. / McConnell, D.B.
History
DepositionJul 12, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 20, 2019Provider: repository / Type: Initial release
Revision 1.1Dec 4, 2019Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name
Revision 1.2May 15, 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

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Assembly

Deposited unit
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,8873
Polymers37,4221
Non-polymers4652
Water36020
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area200 Å2
ΔGint1 kcal/mol
Surface area15840 Å2
MethodPISA
Unit cell
Length a, b, c (Å)145.447, 145.447, 145.447
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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: 37422.363 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN MUTANT / 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-L1K / ~{N}-[1-(2-methyl-2-oxidanyl-propyl)benzimidazol-2-yl]-2-phenyl-pyridine-4-carboxamide


Mass: 386.446 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H22N4O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 20 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 64.84 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5 / Details: 10 % PEG 10000 8 % ethylene glycol 0.1 M HEPES

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.999999701977 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Dec 8, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.999999701977 Å / Relative weight: 1
ReflectionResolution: 2.73→102.85 Å / Num. obs: 13483 / % possible obs: 95.9 % / Redundancy: 4.3 % / Biso Wilson estimate: 59.912 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.059 / Rrim(I) all: 0.067 / Χ2: 0.984 / Net I/σ(I): 18.57 / Num. measured all: 57792 / Scaling rejects: 9
Reflection shellResolution: 2.73→102.85 Å / Redundancy: 4.3 % / Rmerge(I) obs: 0.42 / Mean I/σ(I) obs: 53.63 / Num. unique obs: 54 / CC1/2: 0.999 / Rrim(I) all: 0.022 / % possible all: 87.3

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
REFMAC5.8.0049refinement
PDB_EXTRACT3.25data extraction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: NONE

Resolution: 2.73→102.85 Å / Cor.coef. Fo:Fc: 0.941 / Cor.coef. Fo:Fc free: 0.93 / SU B: 22.031 / SU ML: 0.21 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.493 / ESU R Free: 0.273
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2248 707 5.2 %RANDOM
Rwork0.2002 ---
obs0.2015 12776 98.32 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 129.08 Å2 / Biso mean: 64.013 Å2 / Biso min: 36.87 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refinement stepCycle: final / Resolution: 2.73→102.85 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2416 0 33 20 2469
Biso mean--75.56 47.83 -
Num. residues----301
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0192449
X-RAY DIFFRACTIONr_bond_other_d0.0010.022381
X-RAY DIFFRACTIONr_angle_refined_deg1.2621.9923327
X-RAY DIFFRACTIONr_angle_other_deg2.53335465
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7565301
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.12424.19493
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.09815426
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.3981512
X-RAY DIFFRACTIONr_chiral_restr0.0720.2378
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.0212693
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02517
LS refinement shellResolution: 2.733→2.804 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.405 46 -
Rwork0.315 892 -
all-938 -
obs--93.99 %
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)
19.61834.10216.78385.523.062310.04340.20480.1132-0.3747-0.1450.16150.00170.11070.0047-0.36620.12750.0890.02420.1124-0.01260.1355-45.066-64.1752.079
27.562-0.74450.66012.55492.59463.032-0.1057-0.08431.4272-0.12-0.0126-0.143-0.3704-0.09470.11830.42050.05710.00980.2547-0.07490.3613-29.555-51.4166.994
32.8147-0.004-0.94572.47970.23544.95370.20410.10110.2742-0.0857-0.0671-0.0925-0.3957-0.268-0.13690.05950.05210.03560.0952-0.01710.0832-21.794-60.754-16.462
46.17981.85562.369313.25790.839214.0182-0.0127-0.42030.43140.3470.1094-0.0778-0.03280.0631-0.09660.24890.08150.06970.2094-0.01250.1703-22.048-62.78114.241
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 705
2X-RAY DIFFRACTION2A706 - 794
3X-RAY DIFFRACTION3A795 - 1000
4X-RAY DIFFRACTION4A1001 - 1030

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