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Yorodumi- PDB-8tu5: Bruton's tyrosine kinase in complex with covalent inhibitor compo... -
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-Basic information
Entry | Database: PDB / ID: 8tu5 | ||||||
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Title | Bruton's tyrosine kinase in complex with covalent inhibitor compound 27 | ||||||
Components | Tyrosine-protein kinase BTK | ||||||
Keywords | TRANSFERASE/INHIBITOR / kinase / 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 / positive regulation of synoviocyte proliferation / histamine secretion by mast cell ...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 / positive regulation of synoviocyte proliferation / histamine secretion by mast cell / 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) / positive regulation of immunoglobulin production / 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 / negative regulation of B cell proliferation / Fc-epsilon receptor signaling pathway / B cell activation / mesoderm development / phosphatidylinositol-3,4,5-trisphosphate binding / phospholipase binding / 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 / apoptotic signaling pathway / FCGR3A-mediated phagocytosis / B cell receptor signaling pathway / non-specific protein-tyrosine kinase / calcium-mediated signaling / non-membrane spanning protein tyrosine kinase activity / Regulation of actin dynamics for phagocytic cup formation / G beta:gamma signalling through BTK / positive regulation of interleukin-6 production / cellular response to reactive oxygen species / peptidyl-tyrosine phosphorylation / positive regulation of tumor necrosis factor production / G alpha (12/13) signalling events / DAP12 signaling / positive regulation of NF-kappaB transcription factor activity / T cell receptor signaling pathway / ER-Phagosome pathway / cytoplasmic vesicle / protein tyrosine kinase activity / G alpha (q) signalling events / adaptive immune response / response to lipopolysaccharide / Potential therapeutics for SARS / intracellular signal transduction / membrane raft / protein phosphorylation / innate immune response / perinuclear region of cytoplasm / ATP binding / identical protein binding / nucleus / metal ion binding / plasma membrane / cytosol / cytoplasm Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å | ||||||
Authors | Metrick, C.M. | ||||||
Funding support | 1items
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Citation | Journal: J.Med.Chem. / Year: 2024 Title: Discovery and Preclinical Characterization of BIIB129, a Covalent, Selective, and Brain-Penetrant BTK Inhibitor for the Treatment of Multiple Sclerosis. Authors: Himmelbauer, M.K. / Bajrami, B. / Basile, R. / Capacci, A. / Chen, T. / Choi, C.K. / Gilfillan, R. / Gonzalez-Lopez de Turiso, F. / Gu, C. / Hoemberger, M. / Johnson, D.S. / Jones, J.H. / ...Authors: Himmelbauer, M.K. / Bajrami, B. / Basile, R. / Capacci, A. / Chen, T. / Choi, C.K. / Gilfillan, R. / Gonzalez-Lopez de Turiso, F. / Gu, C. / Hoemberger, M. / Johnson, D.S. / Jones, J.H. / Kadakia, E. / Kirkland, M. / Lin, E.Y. / Liu, Y. / Ma, B. / Magee, T. / Mantena, S. / Marx, I.E. / Metrick, C.M. / Mingueneau, M. / Murugan, P. / Muste, C.A. / Nadella, P. / Nevalainen, M. / Parker Harp, C.R. / Pattaropong, V. / Pietrasiewicz, A. / Prince, R.J. / Purgett, T.J. / Santoro, J.C. / Schulz, J. / Sciabola, S. / Tang, H. / Vandeveer, H.G. / Wang, T. / Yousaf, Z. / Helal, C.J. / Hopkins, B.T. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8tu5.cif.gz | 128.8 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8tu5.ent.gz | 86.5 KB | Display | PDB format |
PDBx/mmJSON format | 8tu5.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8tu5_validation.pdf.gz | 762.9 KB | Display | wwPDB validaton report |
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Full document | 8tu5_full_validation.pdf.gz | 764.3 KB | Display | |
Data in XML | 8tu5_validation.xml.gz | 11.5 KB | Display | |
Data in CIF | 8tu5_validation.cif.gz | 15.3 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/tu/8tu5 ftp://data.pdbj.org/pub/pdb/validation_reports/tu/8tu5 | HTTPS FTP |
-Related structure data
Related structure data | 8tu3C 8tu4C 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: 32680.471 Da / Num. of mol.: 1 / Fragment: Protein kinase domain residues 382-659 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-V7I / Mass: 380.444 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H24N6O2 / Feature type: SUBJECT OF INVESTIGATION |
#3: 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: 2.09 Å3/Da / Density % sol: 41.28 % |
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Crystal grow | Temperature: 277 K / Method: vapor diffusion, sitting drop / Details: bis-tris pH 6.5, ammonium tartrate, PEG 3350 |
-Data collection
Diffraction | Mean temperature: 100 K / Serial crystal experiment: N |
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Diffraction source | Source: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.999 Å |
Detector | Type: DECTRIS PILATUS 12M / Detector: PIXEL / Date: Mar 27, 2021 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 0.999 Å / Relative weight: 1 |
Reflection | Resolution: 2.1→50 Å / Num. obs: 28391 / % possible obs: 99.1 % / Redundancy: 3.15 % / Biso Wilson estimate: 35.02 Å2 / CC1/2: 0.99 / Net I/σ(I): 5.15 |
Reflection shell | Resolution: 2.1→2.23 Å / Num. unique obs: 4616 / CC1/2: 0.535 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.1→40.08 Å / SU ML: 0.2722 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 32.1614 Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
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Solvent computation | Shrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 39.88 Å2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: LAST / Resolution: 2.1→40.08 Å
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Refine LS restraints |
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LS refinement shell |
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Refinement TLS params. | Method: refined / Refine-ID: X-RAY DIFFRACTION
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Refinement TLS group | Refine-ID: X-RAY DIFFRACTION / Auth asym-ID: A / Label asym-ID: A
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