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Yorodumi- PDB-6t3c: Crystal structure of PI3Kgamma in complex with DNA-PK inhibitor A... -
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-Basic information
Entry | Database: PDB / ID: 6t3c | ||||||
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Title | Crystal structure of PI3Kgamma in complex with DNA-PK inhibitor AZD7648 | ||||||
Components | Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform | ||||||
Keywords | TRANSFERASE / kinase fold / type I kinase inhibitor / structure based drug design | ||||||
Function / homology | Function and homology information secretory granule localization / negative regulation of triglyceride catabolic process / natural killer cell chemotaxis / neutrophil extravasation / phosphatidylinositol-4-phosphate 3-kinase / positive regulation of acute inflammatory response / respiratory burst involved in defense response / negative regulation of cardiac muscle contraction / regulation of calcium ion transmembrane transport / T cell chemotaxis ...secretory granule localization / negative regulation of triglyceride catabolic process / natural killer cell chemotaxis / neutrophil extravasation / phosphatidylinositol-4-phosphate 3-kinase / positive regulation of acute inflammatory response / respiratory burst involved in defense response / negative regulation of cardiac muscle contraction / regulation of calcium ion transmembrane transport / T cell chemotaxis / negative regulation of fibroblast apoptotic process / phosphatidylinositol 3-kinase complex, class IB / sphingosine-1-phosphate receptor signaling pathway / phosphatidylinositol 3-kinase complex, class IA / dendritic cell chemotaxis / 1-phosphatidylinositol-4-phosphate 3-kinase activity / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / phosphatidylinositol-4,5-bisphosphate 3-kinase / phosphatidylinositol 3-kinase / phosphatidylinositol-3-phosphate biosynthetic process / 1-phosphatidylinositol-3-kinase activity / mast cell degranulation / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / hepatocyte apoptotic process / positive regulation of Rac protein signal transduction / phosphatidylinositol-mediated signaling / phosphatidylinositol phosphate biosynthetic process / regulation of cell adhesion mediated by integrin / Synthesis of PIPs at the plasma membrane / regulation of angiogenesis / T cell proliferation / cellular response to cAMP / GPVI-mediated activation cascade / T cell activation / ephrin receptor binding / positive regulation of endothelial cell migration / neutrophil chemotaxis / phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of cytokine production / positive regulation of MAP kinase activity / platelet aggregation / endocytosis / G beta:gamma signalling through PI3Kgamma / Signaling by CSF1 (M-CSF) in myeloid cells / kinase activity / positive regulation of cytosolic calcium ion concentration / angiogenesis / adaptive immune response / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / non-specific serine/threonine protein kinase / protein kinase activity / inflammatory response / immune response / G protein-coupled receptor signaling pathway / phosphorylation / protein serine kinase activity / innate immune response / protein serine/threonine kinase activity / ATP binding / membrane / identical protein binding / plasma membrane / cytosol / cytoplasm Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.62 Å | ||||||
Authors | Schimpl, M. / Goldberg, F.W. / Finlay, M.R.V. / Ting, A.K.T. / Beattie, D. / Lamont, G.M. / Fallan, C. / Wrigley, G.L. / Howard, M.R. / Williamson, B. ...Schimpl, M. / Goldberg, F.W. / Finlay, M.R.V. / Ting, A.K.T. / Beattie, D. / Lamont, G.M. / Fallan, C. / Wrigley, G.L. / Howard, M.R. / Williamson, B. / Davies, B.R. / Cadogan, E.B. / Ramos-Montoya, A. / Dean, E. | ||||||
Citation | Journal: J.Med.Chem. / Year: 2020 Title: The Discovery of 7-Methyl-2-[(7-methyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (AZD7648), a Potent and Selective DNA-Dependent Protein ...Title: The Discovery of 7-Methyl-2-[(7-methyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (AZD7648), a Potent and Selective DNA-Dependent Protein Kinase (DNA-PK) Inhibitor. Authors: Goldberg, F.W. / Finlay, M.R.V. / Ting, A.K.T. / Beattie, D. / Lamont, G.M. / Fallan, C. / Wrigley, G.L. / Schimpl, M. / Howard, M.R. / Williamson, B. / Vazquez-Chantada, M. / Barratt, D.G. ...Authors: Goldberg, F.W. / Finlay, M.R.V. / Ting, A.K.T. / Beattie, D. / Lamont, G.M. / Fallan, C. / Wrigley, G.L. / Schimpl, M. / Howard, M.R. / Williamson, B. / Vazquez-Chantada, M. / Barratt, D.G. / Davies, B.R. / Cadogan, E.B. / Ramos-Montoya, A. / Dean, E. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 6t3c.cif.gz | 351.1 KB | Display | PDBx/mmCIF format |
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PDB format | pdb6t3c.ent.gz | 282.9 KB | Display | PDB format |
PDBx/mmJSON format | 6t3c.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/t3/6t3c ftp://data.pdbj.org/pub/pdb/validation_reports/t3/6t3c | HTTPS FTP |
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-Related structure data
Related structure data | 6t2wC 6t3bC 4fhkS C: citing same article (ref.) S: Starting model for refinement |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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Unit cell |
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-Components
#1: Protein | Mass: 110727.102 Da / Num. of mol.: 1 / Fragment: amino acids 144-1102 Source method: isolated from a genetically manipulated source Details: amino acids 144-1102 of human PI3 kinase subunit gamma Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3CG / Cell line (production host): Sf21 / Production host: Spodoptera frugiperda (fall armyworm) References: UniProt: P48736, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase |
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#2: Chemical | ChemComp-MBW / |
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: 2.23 Å3/Da / Density % sol: 44.79 % / Mosaicity: 0.54 ° |
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Crystal grow | Temperature: 293 K / Method: vapor diffusion / pH: 8 Details: 20 % PEG3350, 0.175 M ammonium sulfate, 0.001 M TCEP, 0.1 M Hepes pH 8.0 |
-Data collection
Diffraction | Mean temperature: 100 K / Serial crystal experiment: N |
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Diffraction source | Source: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97626 Å |
Detector | Type: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Feb 14, 2019 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 0.97626 Å / Relative weight: 1 |
Reflection | Resolution: 2.62→39.979 Å / Num. obs: 22763 / % possible obs: 91.7 % / Redundancy: 3.2 % / Biso Wilson estimate: 83.01 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.058 / Rpim(I) all: 0.038 / Rrim(I) all: 0.07 / Net I/σ(I): 9.7 |
Reflection shell | Resolution: 2.62→2.87 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.861 / Mean I/σ(I) obs: 1.2 / Num. unique obs: 1139 / CC1/2: 0.388 / Rpim(I) all: 0.559 / Rrim(I) all: 1.03 / % possible all: 44.5 |
-Phasing
Phasing | Method: molecular replacement | |||||||||
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Phasing MR | Model details: Phaser MODE: MR_AUTO
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-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: 4FHK Resolution: 2.62→38.74 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.932 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.344
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Displacement parameters | Biso max: 235.42 Å2 / Biso min: 53.15 Å2
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Refine analyze | Luzzati coordinate error obs: 0.37 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: final / Resolution: 2.62→38.74 Å
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Refine LS restraints |
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LS refinement shell | Resolution: 2.62→2.8 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
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Refinement TLS params. | Method: refined / Origin x: 160.8663 Å / Origin y: -0.7577 Å / Origin z: 132.2186 Å
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Refinement TLS group | Selection details: { A|* } |