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Yorodumi- PDB-8a2b: EGFR kinase domain (L858R/V948R) in complex with 2-(6,7-dihydro-5... -
+Open data
-Basic information
Entry | Database: PDB / ID: 8a2b | ||||||
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Title | EGFR kinase domain (L858R/V948R) in complex with 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-1-oxo-4-(trifluoromethyl)isoindolin-2-yl]-N-thiazol-2-yl-acetamide | ||||||
Components | Epidermal growth factor receptor | ||||||
Keywords | TRANSFERASE / KINASE 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 | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.69 Å | ||||||
Authors | Kuglstatter, A. / Ehler, A. | ||||||
Funding support | Switzerland, 1items
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Citation | Journal: J.Med.Chem. / Year: 2022 Title: Discovery of Novel Allosteric EGFR L858R Inhibitors for the Treatment of Non-Small-Cell Lung Cancer as a Single Agent or in Combination with Osimertinib. Authors: Obst-Sander, U. / Ricci, A. / Kuhn, B. / Friess, T. / Koldewey, P. / Kuglstatter, A. / Hewings, D. / Goergler, A. / Steiner, S. / Rueher, D. / Imhoff, M.P. / Raschetti, N. / Marty, H.P. / ...Authors: Obst-Sander, U. / Ricci, A. / Kuhn, B. / Friess, T. / Koldewey, P. / Kuglstatter, A. / Hewings, D. / Goergler, A. / Steiner, S. / Rueher, D. / Imhoff, M.P. / Raschetti, N. / Marty, H.P. / Dietzig, A. / Rynn, C. / Ehler, A. / Burger, D. / Kornacker, M. / Schaffland, J.P. / Herting, F. / Pao, W. / Bischoff, J.R. / Martoglio, B. / Alice Nagel, Y. / Jaeschke, G. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8a2b.cif.gz | 108.3 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8a2b.ent.gz | 77.2 KB | Display | PDB format |
PDBx/mmJSON format | 8a2b.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/a2/8a2b ftp://data.pdbj.org/pub/pdb/validation_reports/a2/8a2b | HTTPS FTP |
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-Related structure data
Related structure data | 8a27SC 8a2aC 8a2dC S: Starting model for refinement C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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Unit cell |
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Components on special symmetry positions |
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-Components
#1: Protein | Mass: 37327.199 Da / Num. of mol.: 1 / Mutation: L858R, V948R 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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#2: Chemical | ChemComp-KY9 / ( |
#3: Water | ChemComp-HOH / |
Has ligand of interest | Y |
-Experimental details
-Experiment
Experiment | Method: X-RAY DIFFRACTION / Number of used crystals: 1 |
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-Sample preparation
Crystal | Density Matthews: 2.36 Å3/Da / Density % sol: 47.92 % |
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Crystal grow | Temperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8 Details: 25% PEG Smear High, 0.1M Tris, 0.2M magnesium chloride, 10% glycerole |
-Data collection
Diffraction | Mean temperature: 100 K / Serial crystal experiment: N |
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Diffraction source | Source: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å |
Detector | Type: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 16, 2019 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 1 Å / Relative weight: 1 |
Reflection | Resolution: 1.69→65.29 Å / Num. obs: 27062 / % possible obs: 93.3 % / Redundancy: 18.5 % / CC1/2: 1 / Net I/σ(I): 25.1 |
Reflection shell | Resolution: 1.69→1.88 Å / Num. unique obs: 1429 / CC1/2: 0.68 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: 8A27 Resolution: 1.69→65.29 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.921 / SU B: 6.655 / SU ML: 0.102 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.153 / ESU R Free: 0.15 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: U VALUES : WITH TLS ADDED
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Solvent computation | Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK | |||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso max: 111.71 Å2 / Biso mean: 32.128 Å2 / Biso min: 10.46 Å2
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Refinement step | Cycle: final / Resolution: 1.69→65.29 Å
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Refine LS restraints |
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LS refinement shell | Resolution: 1.695→1.739 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
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Refinement TLS params. | Method: refined / Origin x: -3.4716 Å / Origin y: -29.6374 Å / Origin z: 3.9633 Å
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