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Yorodumi- PDB-4rfz: Crystal structure of BTK kinase domain complexed with 6-(dimethyl... -
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-Basic information
Entry | Database: PDB / ID: 4rfz | ||||||
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Title | Crystal structure of BTK kinase domain complexed with 6-(dimethylamino)-8-fluoro-2-[2-(hydroxymethyl)-3-[1-methyl-5-[[5-(morpholine-4-carbonyl)-2-pyridyl]amino]-6-oxo-3-pyridyl]phenyl]isoquinolin-1-one | ||||||
Components | Tyrosine-protein kinase BTK | ||||||
Keywords | TRANSFERASE/TRANSFERASE INHIBITOR / TRANSFERASE-TRANSFERASE INHIBITOR complex | ||||||
Function / homology | Function and homology information regulation of B cell cytokine production / proteoglycan catabolic process / monocyte proliferation / positive regulation of interleukin-17A production / regulation of B cell apoptotic process / eosinophil homeostasis / positive regulation of type III hypersensitivity / B cell affinity maturation / histamine secretion by mast cell / positive regulation of synoviocyte proliferation ...regulation of B cell cytokine production / proteoglycan catabolic process / monocyte proliferation / positive regulation of interleukin-17A production / regulation of B cell apoptotic process / eosinophil homeostasis / positive regulation of type III hypersensitivity / B cell affinity maturation / histamine secretion by mast cell / positive regulation of synoviocyte proliferation / neutrophil homeostasis / cellular response to molecule of fungal origin / positive regulation of type I hypersensitivity / cellular response to interleukin-7 / MyD88 deficiency (TLR2/4) / MyD88-dependent toll-like receptor signaling pathway / IRAK4 deficiency (TLR2/4) / MyD88:MAL(TIRAP) cascade initiated on plasma membrane / positive regulation of B cell differentiation / positive regulation of NLRP3 inflammasome complex assembly / phospholipase activator activity / negative regulation of interleukin-10 production / B cell activation / negative regulation of B cell proliferation / Fc-epsilon receptor signaling pathway / phosphatidylinositol-3,4,5-trisphosphate binding / phospholipase binding / mesoderm development / positive regulation of immunoglobulin production / RHO GTPases Activate WASPs and WAVEs / positive regulation of phagocytosis / positive regulation of B cell proliferation / cell maturation / FCERI mediated Ca+2 mobilization / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / calcium-mediated signaling / apoptotic signaling pathway / FCGR3A-mediated phagocytosis / B cell receptor signaling pathway / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / G beta:gamma signalling through BTK / Regulation of actin dynamics for phagocytic cup formation / cellular response to reactive oxygen species / positive regulation of interleukin-6 production / peptidyl-tyrosine phosphorylation / G alpha (12/13) signalling events / positive regulation of tumor necrosis factor production / DAP12 signaling / positive regulation of NF-kappaB transcription factor activity / ER-Phagosome pathway / T cell receptor signaling pathway / cytoplasmic vesicle / G alpha (q) signalling events / protein tyrosine kinase activity / Potential therapeutics for SARS / response to lipopolysaccharide / adaptive immune response / intracellular signal transduction / membrane raft / protein phosphorylation / innate immune response / perinuclear region of cytoplasm / ATP binding / identical protein binding / metal ion binding / nucleus / plasma membrane / cytosol / cytoplasm Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.17 Å | ||||||
Authors | Kuglstatter, A. / Wong, A. | ||||||
Citation | Journal: Bioorg.Med.Chem.Lett. / Year: 2015 Title: Finding the perfect spot for fluorine: Improving potency up to 40-fold during a rational fluorine scan of a Bruton's Tyrosine Kinase (BTK) inhibitor scaffold. Authors: Lou, Y. / Sweeney, Z.K. / Kuglstatter, A. / Davis, D. / Goldstein, D.M. / Han, X. / Hong, J. / Kocer, B. / Kondru, R.K. / Litman, R. / McIntosh, J. / Sarma, K. / Suh, J. / Taygerly, J. / Owens, T.D. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 4rfz.cif.gz | 137.6 KB | Display | PDBx/mmCIF format |
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PDB format | pdb4rfz.ent.gz | 105.3 KB | Display | PDB format |
PDBx/mmJSON format | 4rfz.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/rf/4rfz ftp://data.pdbj.org/pub/pdb/validation_reports/rf/4rfz | HTTPS FTP |
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-Related structure data
Related structure data | 4rfyC 4rg0C 4otrS S: Starting model for refinement C: citing same article (ref.) |
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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 on special symmetry positions |
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-Components
#1: Protein | Mass: 32521.135 Da / Num. of mol.: 1 / Fragment: protein kinase domain (UNP residues 378-659) / Mutation: M489A, R492A, E624A, K625A Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: BTK, AGMX1, ATK, BPK / Production host: Spodoptera frugiperda (fall armyworm) References: UniProt: Q06187, non-specific protein-tyrosine kinase | ||
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#2: Chemical | ChemComp-3OV / | ||
#3: Chemical | #4: Water | ChemComp-HOH / | |
-Experimental details
-Experiment
Experiment | Method: X-RAY DIFFRACTION / Number of used crystals: 1 |
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-Sample preparation
Crystal | Density Matthews: 2.24 Å3/Da / Density % sol: 45.2 % |
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Crystal grow | Temperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8 Details: 33% PEG3350, 0.1 M HEPES, pH 8.0, VAPOR DIFFUSION, HANGING DROP, temperature 293K |
-Data collection
Diffraction | Mean temperature: 100 K |
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Diffraction source | Source: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å |
Detector | Type: ADSC QUANTUM 315r / Detector: CCD |
Radiation | Monochromator: liquid nitrogen cooled dual crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 1 Å / Relative weight: 1 |
Reflection | Resolution: 1.17→50 Å / Num. obs: 86470 / % possible obs: 87.5 % / Redundancy: 4.8 % / Biso Wilson estimate: 10.6 Å2 / Rsym value: 0.046 / Net I/σ(I): 21.8 |
Reflection shell | Resolution: 1.17→1.21 Å / Redundancy: 2.8 % / Mean I/σ(I) obs: 1.8 / Rsym value: 0.432 / % possible all: 38.1 |
-Processing
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Refinement | Method to determine structure: FOURIER SYNTHESIS Starting model: PDB ENTRY 4OTR Resolution: 1.17→42.72 Å / Cor.coef. Fo:Fc: 0.972 / Cor.coef. Fo:Fc free: 0.967 / SU B: 1.379 / SU ML: 0.027 / Cross valid method: THROUGHOUT / ESU R: 0.04 / ESU R Free: 0.04 / Stereochemistry target values: MAXIMUM LIKELIHOOD
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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 mean: 18.282 Å2
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Refinement step | Cycle: LAST / Resolution: 1.17→42.72 Å
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