+Open data
-Basic information
Entry | Database: PDB / ID: 8d76 | ||||||
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Title | Crystal Structure of EGFR LRTM with compound 24 | ||||||
Components | Epidermal growth factor receptor | ||||||
Keywords | SIGNALING PROTEIN / Protein Kinase / inhibitor / kinase domain / mutation | ||||||
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: 2.4 Å | ||||||
Authors | Kim, J.L. | ||||||
Funding support | 1items
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Citation | Journal: J.Med.Chem. / Year: 2022 Title: Discovery of BLU-945, a Reversible, Potent, and Wild-Type-Sparing Next-Generation EGFR Mutant Inhibitor for Treatment-Resistant Non-Small-Cell Lung Cancer. Authors: Eno, M.S. / Brubaker, J.D. / Campbell, J.E. / De Savi, C. / Guzi, T.J. / Williams, B.D. / Wilson, D. / Wilson, K. / Brooijmans, N. / Kim, J. / Ozen, A. / Perola, E. / Hsieh, J. / Brown, V. / ...Authors: Eno, M.S. / Brubaker, J.D. / Campbell, J.E. / De Savi, C. / Guzi, T.J. / Williams, B.D. / Wilson, D. / Wilson, K. / Brooijmans, N. / Kim, J. / Ozen, A. / Perola, E. / Hsieh, J. / Brown, V. / Fetalvero, K. / Garner, A. / Zhang, Z. / Stevison, F. / Woessner, R. / Singh, J. / Timsit, Y. / Kinkema, C. / Medendorp, C. / Lee, C. / Albayya, F. / Zalutskaya, A. / Schalm, S. / Dineen, T.A. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8d76.cif.gz | 159.8 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8d76.ent.gz | 122.2 KB | Display | PDB format |
PDBx/mmJSON format | 8d76.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/d7/8d76 ftp://data.pdbj.org/pub/pdb/validation_reports/d7/8d76 | HTTPS FTP |
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-Related structure data
Related structure data | 8d73C 4i22S 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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2 |
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Unit cell |
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Noncrystallographic symmetry (NCS) | NCS domain:
NCS domain segments: Component-ID: 0 / Ens-ID: 1 / Beg auth comp-ID: LEU / Beg label comp-ID: LEU / End auth comp-ID: ALA / End label comp-ID: ALA / Refine code: 0 / Auth seq-ID: 703 - 1013 / Label seq-ID: 29 - 339
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-Components
#1: Protein | Mass: 39797.777 Da / Num. of mol.: 2 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-GOL / #3: Chemical | #4: Water | ChemComp-HOH / | Has ligand of interest | Y | |
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-Experimental details
-Experiment
Experiment | Method: X-RAY DIFFRACTION / Number of used crystals: 1 |
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-Sample preparation
Crystal | Density Matthews: 2.14 Å3/Da / Density % sol: 42.45 % |
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Crystal grow | Temperature: 285 K / Method: vapor diffusion, hanging drop / pH: 8 Details: 0.1 M sodium acetate pH 5.3, 0.2 M potassium acetate, 3% PEG 8000. |
-Data collection
Diffraction | Mean temperature: 110 K / Ambient temp details: 2018-07-18 / Serial crystal experiment: N |
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Diffraction source | Source: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.9159 Å |
Detector | Type: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Jul 18, 2018 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 0.9159 Å / Relative weight: 1 |
Reflection | Resolution: 2.39→48.7 Å / Num. obs: 25531 / % possible obs: 98 % / Redundancy: 3.5 % / Rrim(I) all: 0.08 / Net I/σ(I): 10.8 |
Reflection shell | Resolution: 2.39→2.43 Å / Redundancy: 3.5 % / Mean I/σ(I) obs: 2.2 / Num. unique obs: 1289 / Rrim(I) all: 0.63 / % possible all: 96.9 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: 4i22 Resolution: 2.4→30 Å / Cor.coef. Fo:Fc: 0.97 / Cor.coef. Fo:Fc free: 0.913 / SU B: 11.121 / SU ML: 0.247 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 1.161 / ESU R Free: 0.315 / Stereochemistry target values: MAXIMUM LIKELIHOOD Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
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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: BABINET MODEL WITH MASK | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso max: 157.35 Å2 / Biso mean: 61.506 Å2 / Biso min: 33.84 Å2
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Refinement step | Cycle: final / Resolution: 2.4→30 Å
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Refine LS restraints |
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Refine LS restraints NCS | Ens-ID: 1 / Number: 10398 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.05 Å / Weight position: 0.05
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LS refinement shell | Resolution: 2.4→2.462 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
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