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- PDB-5y25: EGFR kinase domain mutant (T790M/L858R) with covalent ligand NS-062 -

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Basic information

Entry
Database: PDB / ID: 5y25
TitleEGFR kinase domain mutant (T790M/L858R) with covalent ligand NS-062
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Inhibitor / complex / TRANSFERASE / 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 / epidermal growth factor receptor activity / EGFR interacts with phospholipase C-gamma / 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 / epidermal growth factor receptor activity / EGFR interacts with phospholipase C-gamma / 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 / 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 / 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 / SHC1 events in EGFR signaling / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / EGFR Transactivation by Gastrin / transmembrane receptor protein tyrosine kinase activity / 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 / positive regulation of epithelial cell proliferation / Signal transduction by L1 / 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 / Signaling by ERBB2 ECD mutants / receptor protein-tyrosine kinase / Signaling by ERBB2 KD Mutants / negative regulation of protein catabolic process / positive regulation of miRNA transcription / kinase binding / ruffle membrane / epidermal growth factor receptor signaling pathway / positive regulation of protein phosphorylation / cell morphogenesis / neuron differentiation / 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 / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / transmembrane signaling receptor activity / positive regulation of canonical Wnt signaling pathway / Clathrin-mediated endocytosis / PIP3 activates AKT signaling / ATPase binding / virus receptor activity / 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-8LU / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.102 Å
AuthorsShiroishi, M. / Abe, Y. / Caaveiro, J.M.M. / Sakamoto, S. / Morimoto, S. / Fuchida, H. / Shindo, N. / Ojida, A.
Funding support Japan, 1items
OrganizationGrant numberCountry
Network Joint Research Center for Materials and Devices (MEXT,Japan) Japan
CitationJournal: Nat.Chem.Biol. / Year: 2019
Title: Selective and reversible modification of kinase cysteines with chlorofluoroacetamides.
Authors: Shindo, N. / Fuchida, H. / Sato, M. / Watari, K. / Shibata, T. / Kuwata, K. / Miura, C. / Okamoto, K. / Hatsuyama, Y. / Tokunaga, K. / Sakamoto, S. / Morimoto, S. / Abe, Y. / Shiroishi, M. / ...Authors: Shindo, N. / Fuchida, H. / Sato, M. / Watari, K. / Shibata, T. / Kuwata, K. / Miura, C. / Okamoto, K. / Hatsuyama, Y. / Tokunaga, K. / Sakamoto, S. / Morimoto, S. / Abe, Y. / Shiroishi, M. / Caaveiro, J.M.M. / Ueda, T. / Tamura, T. / Matsunaga, N. / Nakao, T. / Koyanagi, S. / Ohdo, S. / Yamaguchi, Y. / Hamachi, I. / Ono, M. / Ojida, A.
History
DepositionJul 24, 2017Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 25, 2018Provider: repository / Type: Initial release
Revision 1.1Aug 7, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Nov 22, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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)38,7412
Polymers38,1521
Non-polymers5891
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area14730 Å2
MethodPISA
Unit cell
Length a, b, c (Å)148.291, 148.291, 148.291
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: 38152.160 Da / Num. of mol.: 1 / Fragment: Kinase domain, UNP residues 698-1022 / Mutation: T790M, L858R
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-8LU / (2R)-N-[4-[(3-chloranyl-4-fluoranyl-phenyl)amino]-7-(3-morpholin-4-ylpropoxy)quinazolin-6-yl]-1-(2-fluoranylethanoyl)pyrrolidine-2-carboxamide


Mass: 589.033 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H31ClF2N6O4 / Feature type: SUBJECT OF INVESTIGATION
Has protein modificationY

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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: 3.56 Å3/Da / Density % sol: 69.64 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 100mM HEPES pH7.5, 10% PEG 10000, 8% ethylene glycol

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL26B1 / Wavelength: 1 Å
DetectorType: RAYONIX MX225HE / Detector: CCD / Date: Jul 5, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.1→39.6 Å / Num. obs: 10020 / % possible obs: 100 % / Redundancy: 21.7 % / Rmerge(I) obs: 0.08 / Rpim(I) all: 0.018 / Χ2: 1.207 / Net I/σ(I): 54.39
Reflection shellResolution: 3.1→3.15 Å / Redundancy: 21.4 % / Rmerge(I) obs: 0.585 / Mean I/σ(I) obs: 7.39 / Num. unique obs: 502 / CC1/2: 0.968 / Rpim(I) all: 0.129 / Χ2: 1.012 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.10.1_2155refinement
HKL-2000data reduction
HKL-2000data scaling
PHENIX1.10.1_2155phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5EDP

5edp


Resolution: 3.102→19.816 Å / Cross valid method: FREE R-VALUE / σ(F): 1.36
RfactorNum. reflection% reflection
Rfree0.246 992 9.96 %
Rwork0.2134 --
obs0.2167 9961 99.94 %
Refinement stepCycle: LAST / Resolution: 3.102→19.816 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2312 0 41 0 2353
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0052409
X-RAY DIFFRACTIONf_angle_d0.6963267
X-RAY DIFFRACTIONf_dihedral_angle_d19.3941454
X-RAY DIFFRACTIONf_chiral_restr0.047366
X-RAY DIFFRACTIONf_plane_restr0.005407
LS refinement shellResolution: 3.102→3.2644 Å
RfactorNum. reflection% reflection
Rfree0.3551 139 -
Rwork0.3175 1284 -
obs--100 %

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