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Yorodumi- PDB-4ajw: Discovery and Optimization of New Benzimidazole- and Benzoxazole-... -
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-Basic information
Entry | Database: PDB / ID: 4ajw | ||||||
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Title | Discovery and Optimization of New Benzimidazole- and Benzoxazole-Pyrimidone Selective PI3KBeta Inhibitors for the Treatment of Phosphatase and TENsin homologue (PTEN)-Deficient Cancers | ||||||
Components | PHOSPHATIDYLINOSITOL-4,5-BISPHOSPHATE 3-KINASE CATALYTIC SUBUNIT DELTA ISOFORM | ||||||
Keywords | TRANSFERASE / P110D | ||||||
Function / homology | Function and homology information Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / Interleukin receptor SHC signaling / Synthesis of PIPs at the plasma membrane / PIP3 activates AKT signaling / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / positive regulation of cell migration by vascular endothelial growth factor signaling pathway / Regulation of signaling by CBL / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / Interleukin-3, Interleukin-5 and GM-CSF signaling / RET signaling ...Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / Interleukin receptor SHC signaling / Synthesis of PIPs at the plasma membrane / PIP3 activates AKT signaling / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / positive regulation of cell migration by vascular endothelial growth factor signaling pathway / Regulation of signaling by CBL / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / Interleukin-3, Interleukin-5 and GM-CSF signaling / RET signaling / positive regulation of epithelial tube formation / positive regulation of neutrophil apoptotic process / phosphatidylinositol 3-kinase complex / 1-phosphatidylinositol-4-phosphate 3-kinase activity / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / phosphatidylinositol-4,5-bisphosphate 3-kinase / phosphatidylinositol 3-kinase complex, class IA / phosphatidylinositol 3-kinase / phosphatidylinositol-3-phosphate biosynthetic process / 1-phosphatidylinositol-3-kinase activity / B cell activation / B cell homeostasis / homeostasis of number of cells / defense response to fungus / positive regulation of endothelial cell proliferation / positive regulation of endothelial cell migration / phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of angiogenesis / chemotaxis / kinase activity / adaptive immune response / cell differentiation / cell surface receptor signaling pathway / positive regulation of cell migration / inflammatory response / phosphorylation / negative regulation of gene expression / innate immune response / positive regulation of gene expression / ATP binding / plasma membrane / cytosol / cytoplasm Similarity search - Function | ||||||
Biological species | MUS MUSCULUS (house mouse) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å | ||||||
Authors | Certal, V. / Halley, F. / Virone-Oddos, A. / Delorme, C. / Karlsson, A. / Rak, A. / Thompson, F. / Filoche-Romme, B. / El-Ahmad, Y. / Carry, J.C. ...Certal, V. / Halley, F. / Virone-Oddos, A. / Delorme, C. / Karlsson, A. / Rak, A. / Thompson, F. / Filoche-Romme, B. / El-Ahmad, Y. / Carry, J.C. / Abecassis, P.Y. / Lejeune, P. / Bonnevaux, H. / Nicolas, J.P. / Bertrand, T. / Marquette, J.P. / Michot, N. / Benard, T. / Below, P. / Vade, I. / Chatreaux, F. / Lebourg, G. / Pilorge, F. / Angouillant-Boniface, O. / Louboutin, A. / Lengauer, C. / Schio, L. | ||||||
Citation | Journal: J.Med.Chem. / Year: 2012 Title: Discovery and Optimization of New Benzimidazole- and Benzoxazole-Pyrimidone Selective Pi3Kbeta Inhibitors for the Treatment of Phosphatase and Tensin Homologue (Pten)-Deficient Cancers. Authors: Certal, V. / Halley, F. / Virone-Oddos, A. / Delorme, C. / Karlsson, A. / Rak, A. / Thompson, F. / Filoche-Romm, B. / El-Ahmad, Y. / Carry, J.C. / Abecassis, P.Y. / Lejeune, P. / Vincent, L. ...Authors: Certal, V. / Halley, F. / Virone-Oddos, A. / Delorme, C. / Karlsson, A. / Rak, A. / Thompson, F. / Filoche-Romm, B. / El-Ahmad, Y. / Carry, J.C. / Abecassis, P.Y. / Lejeune, P. / Vincent, L. / Bonnevaux, H. / Nicolas, J.P. / Bertrand, T. / Marquette, J.P. / Michot, N. / Benard, T. / Below, P. / Vade, I. / Chatreaux, F. / Lebourg, G. / Pilorge, F. / Angouillant-Boniface, O. / Louboutin, A. / Lengauer, C. / Schio, L. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 4ajw.cif.gz | 327 KB | Display | PDBx/mmCIF format |
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PDB format | pdb4ajw.ent.gz | 256.7 KB | Display | PDB format |
PDBx/mmJSON format | 4ajw.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/aj/4ajw ftp://data.pdbj.org/pub/pdb/validation_reports/aj/4ajw | HTTPS FTP |
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-Related structure data
Related structure data | 2wxfS S: Starting model for refinement |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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2 |
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Unit cell |
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-Components
#1: Protein | Mass: 107210.023 Da / Num. of mol.: 2 / Fragment: RESIDUES 110-1044 Source method: isolated from a genetically manipulated source Source: (gene. exp.) MUS MUSCULUS (house mouse) / Cell line (production host): Sf21 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) References: UniProt: O35904, phosphatidylinositol-4,5-bisphosphate 3-kinase #2: Chemical | #3: Water | ChemComp-HOH / | |
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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: 2.8 Å3/Da / Density % sol: 56 % / Description: NONE |
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Crystal grow | pH: 6.5 Details: 14-16% PEG 8000 28-32% ETHYLENE GLYCOL 100 MM CARBOXYLIC ACIDS 100 MM MES/IMIDAZOLE, PH 6.5 |
-Data collection
Diffraction | Mean temperature: 100 K |
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Diffraction source | Source: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 0.9784 |
Detector | Type: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 26, 2011 / Details: MIRRORS |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 0.9784 Å / Relative weight: 1 |
Reflection | Resolution: 2.8→71.6 Å / Num. obs: 47547 / % possible obs: 98.4 % / Observed criterion σ(I): 2 / Redundancy: 3.3 % / Biso Wilson estimate: 84.98 Å2 / Rmerge(I) obs: 0.07 / Net I/σ(I): 10.1 |
Reflection shell | Resolution: 2.8→2.87 Å / Redundancy: 3.4 % / Rmerge(I) obs: 0.47 / Mean I/σ(I) obs: 2.4 / % possible all: 99.5 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: PDB ENTRY 2WXF Resolution: 2.8→71.57 Å / Cor.coef. Fo:Fc: 0.8736 / Cor.coef. Fo:Fc free: 0.8569 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.383
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Displacement parameters | Biso mean: 74.83 Å2
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Refinement step | Cycle: LAST / Resolution: 2.8→71.57 Å
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Refine LS restraints |
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LS refinement shell | Resolution: 2.8→2.87 Å / Total num. of bins used: 20
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