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Yorodumi- PDB-8po1: Discovery and Optimisation of Potent, Efficacious and Selective I... -
+Open data
-Basic information
Entry | Database: PDB / ID: 8po1 | ||||||
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Title | Discovery and Optimisation of Potent, Efficacious and Selective Inhibitors Targeting EGFR Exon20 Insertion Mutations. Compound 22 bound to EGFRinsNPG [V948R] | ||||||
Components | Epidermal growth factor receptor | ||||||
Keywords | SIGNALING PROTEIN / EGFR / Exon 20 insertion / non-small cell lung cancer / oncology | ||||||
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 / 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 / eyelid development in camera-type eye / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / protein insertion into membrane / cerebral cortex cell migration / ERBB2 Regulates Cell Motility / Respiratory syncytial virus (RSV) attachment and entry / 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 / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / MAP kinase kinase kinase activity / embryonic placenta development / positive regulation of bone resorption / positive regulation of G1/S transition of mitotic cell cycle / GAB1 signalosome / 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 / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / cellular response to cadmium ion / EGFR Transactivation by Gastrin / positive regulation of DNA repair / 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 / positive regulation of synaptic transmission, glutamatergic / cellular response to dexamethasone stimulus / ossification / neurogenesis / regulation of ERK1 and ERK2 cascade / basal plasma membrane / neuron projection morphogenesis / positive regulation of superoxide anion generation / positive regulation of DNA replication / epithelial cell proliferation / Signal transduction by L1 / cellular response to estradiol stimulus / positive regulation of epithelial cell proliferation / NOTCH3 Activation and Transmission of Signal to the Nucleus / astrocyte activation / liver regeneration / positive regulation of protein localization to plasma membrane / EGFR downregulation / 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 / lung development / clathrin-coated endocytic vesicle membrane / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / epidermal growth factor receptor signaling pathway / negative regulation of protein catabolic process / receptor protein-tyrosine kinase / Downregulation of ERBB2 signaling / kinase binding / ruffle membrane / positive regulation of miRNA transcription / cell-cell adhesion Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.11 Å | ||||||
Authors | Hargreaves, D. | ||||||
Funding support | 1items
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Citation | Journal: J.Med.Chem. / Year: 2024 Title: Discovery and Optimization of Potent, Efficacious and Selective Inhibitors Targeting EGFR Exon20 Insertion Mutations. Authors: Thomson, C. / Barton, P. / Braybrooke, E. / Colclough, N. / Dong, Z. / Evans, L. / Floc'h, N. / Guerot, C. / Hargreaves, D. / Khurana, P. / Li, S. / Li, X. / Lister, A. / McCoull, W. / ...Authors: Thomson, C. / Barton, P. / Braybrooke, E. / Colclough, N. / Dong, Z. / Evans, L. / Floc'h, N. / Guerot, C. / Hargreaves, D. / Khurana, P. / Li, S. / Li, X. / Lister, A. / McCoull, W. / McWilliams, L. / Orme, J.P. / Packer, M.J. / Swaih, A.M. / Ward, R.A. / Winlow, P. / Ye, Y. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8po1.cif.gz | 78 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8po1.ent.gz | 54.8 KB | Display | PDB format |
PDBx/mmJSON format | 8po1.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8po1_validation.pdf.gz | 706.2 KB | Display | wwPDB validaton report |
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Full document | 8po1_full_validation.pdf.gz | 711 KB | Display | |
Data in XML | 8po1_validation.xml.gz | 14.5 KB | Display | |
Data in CIF | 8po1_validation.cif.gz | 20.6 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/po/8po1 ftp://data.pdbj.org/pub/pdb/validation_reports/po/8po1 | HTTPS FTP |
-Related structure data
Related structure data | 8pnzC 8po0C 8po2C 8po3C 8po4C 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
#1: Protein | Mass: 37774.594 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: EGFR, ERBB, ERBB1, HER1 / Production host: Spodoptera frugiperda granulovirus References: UniProt: P00533, receptor protein-tyrosine kinase | ||||
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#2: Chemical | ChemComp-2EI / Mass: 535.636 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H33N5O3 / Feature type: SUBJECT OF INVESTIGATION | ||||
#3: Chemical | ChemComp-IOD / #4: 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: 3.43 Å3/Da / Density % sol: 64.13 % / Description: hexagonal bipyramid |
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Crystal grow | Temperature: 293.15 K / Method: vapor diffusion, sitting drop Details: PEG 8K 10%w/v pH 0, NH4I 0.2M pH 0, PCPT 0.1M pH 7.5 |
-Data collection
Diffraction | Mean temperature: 100 K / Serial crystal experiment: N |
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Diffraction source | Source: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å |
Detector | Type: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 16, 2018 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 0.9795 Å / Relative weight: 1 |
Reflection | Resolution: 2.11→73.17 Å / Num. obs: 27901 / % possible obs: 100 % / Redundancy: 18.2 % / CC1/2: 0.998 / Net I/σ(I): 12.8 |
Reflection shell | Resolution: 2.11→2.16 Å / Num. unique obs: 2279 / CC1/2: 0.533 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.11→25.63 Å / Cor.coef. Fo:Fc: 0.926 / Cor.coef. Fo:Fc free: 0.922 / SU R Cruickshank DPI: 0.199 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.21 / SU Rfree Blow DPI: 0.181 / SU Rfree Cruickshank DPI: 0.176
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Displacement parameters | Biso mean: 46.22 Å2
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Refine analyze | Luzzati coordinate error obs: 0.37 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: LAST / Resolution: 2.11→25.63 Å
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Refine LS restraints |
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LS refinement shell | Resolution: 2.11→2.13 Å / Total num. of bins used: 51
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