+Open data
-Basic information
Entry | Database: PDB / ID: 8br7 | ||||||
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Title | Discovery of IRAK4 Inhibitors BAY1834845 and BAY1830839 | ||||||
Components | Interleukin-1 receptor-associated kinase 4 | ||||||
Keywords | TRANSFERASE / IRAK4 / KINASE | ||||||
Function / homology | Function and homology information IRAK4 deficiency (TLR5) / MyD88 dependent cascade initiated on endosome / TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation / MyD88 cascade initiated on plasma membrane / Toll signaling pathway / neutrophil migration / interleukin-33-mediated signaling pathway / toll-like receptor 9 signaling pathway / neutrophil mediated immunity / interleukin-1 receptor binding ...IRAK4 deficiency (TLR5) / MyD88 dependent cascade initiated on endosome / TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation / MyD88 cascade initiated on plasma membrane / Toll signaling pathway / neutrophil migration / interleukin-33-mediated signaling pathway / toll-like receptor 9 signaling pathway / neutrophil mediated immunity / interleukin-1 receptor binding / interleukin-1-mediated signaling pathway / MyD88-dependent toll-like receptor signaling pathway / IRAK4 deficiency (TLR2/4) / MyD88:MAL(TIRAP) cascade initiated on plasma membrane / toll-like receptor 4 signaling pathway / toll-like receptor signaling pathway / extrinsic component of plasma membrane / JNK cascade / TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling / positive regulation of smooth muscle cell proliferation / cytokine-mediated signaling pathway / Interleukin-1 signaling / PIP3 activates AKT signaling / kinase activity / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / positive regulation of canonical NF-kappaB signal transduction / cellular response to lipopolysaccharide / endosome membrane / non-specific serine/threonine protein kinase / intracellular signal transduction / protein serine kinase activity / innate immune response / protein serine/threonine kinase activity / protein kinase binding / magnesium ion binding / cell surface / extracellular space / ATP binding / nucleus / plasma membrane / cytoplasm / cytosol Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.119 Å | ||||||
Authors | Schafer, M. / Bothe, U. / Schmidt, N. / Gunther, J. / Nubbemeyer, R. / Siebeneicher, H. / Ring, S. / Boemer, U. / Peters, M. / Denner, K. ...Schafer, M. / Bothe, U. / Schmidt, N. / Gunther, J. / Nubbemeyer, R. / Siebeneicher, H. / Ring, S. / Boemer, U. / Peters, M. / Denner, K. / Himmel, H. / Sutter, A. / Terebesi, I. / Lange, M. / Wenger, A.M. / Guimond, N. / Thaler, T. / Platzek, J. / Eberspaecher, U. / Steuber, H. / Steinmeyer, A. / Zollner, T.M. | ||||||
Funding support | 1items
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Citation | Journal: J.Med.Chem. / Year: 2024 Title: Discovery of IRAK4 Inhibitors BAY1834845 (Zabedosertib) and BAY1830839 . Authors: Bothe, U. / Gunther, J. / Nubbemeyer, R. / Siebeneicher, H. / Ring, S. / Bomer, U. / Peters, M. / Rausch, A. / Denner, K. / Himmel, H. / Sutter, A. / Terebesi, I. / Lange, M. / Wengner, A.M. ...Authors: Bothe, U. / Gunther, J. / Nubbemeyer, R. / Siebeneicher, H. / Ring, S. / Bomer, U. / Peters, M. / Rausch, A. / Denner, K. / Himmel, H. / Sutter, A. / Terebesi, I. / Lange, M. / Wengner, A.M. / Guimond, N. / Thaler, T. / Platzek, J. / Eberspacher, U. / Schafer, M. / Steuber, H. / Zollner, T.M. / Steinmeyer, A. / Schmidt, N. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8br7.cif.gz | 128.9 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8br7.ent.gz | Display | PDB format | |
PDBx/mmJSON format | 8br7.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8br7_validation.pdf.gz | 898.6 KB | Display | wwPDB validaton report |
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Full document | 8br7_full_validation.pdf.gz | 907.6 KB | Display | |
Data in XML | 8br7_validation.xml.gz | 22.5 KB | Display | |
Data in CIF | 8br7_validation.cif.gz | 29.8 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/br/8br7 ftp://data.pdbj.org/pub/pdb/validation_reports/br/8br7 | HTTPS FTP |
-Related structure data
Related structure data | 8atbC 8atlC 8atnC 8br5C 8br6C 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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2 |
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Unit cell |
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Components on special symmetry positions |
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-Components
#1: Protein | Mass: 33286.582 Da / Num. of mol.: 2 / Mutation: K400A, E401A, E402A Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: IRAK4 / Production host: Spodoptera frugiperda (fall armyworm) References: UniProt: Q9NWZ3, non-specific serine/threonine protein kinase #2: Chemical | #3: Water | ChemComp-HOH / | Has ligand of interest | Y | |
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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: 2.7 Å3/Da / Density % sol: 54.5 % |
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Crystal grow | Temperature: 293 K / Method: vapor diffusion, hanging drop Details: 0.1M sodium acetate buffer at pH 4.9, 1.5-1.7M ammonium citrate and 0.02M hexaaminecobalt(III)chloride |
-Data collection
Diffraction | Mean temperature: 100 K / Serial crystal experiment: N |
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Diffraction source | Source: SYNCHROTRON / Site: PETRA III, EMBL c/o DESY / Beamline: P14 (MX2) / Wavelength: 0.9763 Å |
Detector | Type: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Oct 4, 2021 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 0.9763 Å / Relative weight: 1 |
Reflection | Resolution: 2.119→19.77 Å / Num. obs: 35635 / % possible obs: 86.2 % / Redundancy: 6.49 % / CC1/2: 0.999 / Rrim(I) all: 0.115 / Net I/σ(I): 16.69 |
Reflection shell | Resolution: 2.12→2.25 Å / Mean I/σ(I) obs: 1.66 / Num. unique obs: 5751 / CC1/2: 0.701 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: in house model Resolution: 2.119→19.768 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.93 / WRfactor Rfree: 0.272 / WRfactor Rwork: 0.219 / SU B: 10.535 / SU ML: 0.245 / Average fsc free: 0.7544 / Average fsc work: 0.7705 / Cross valid method: THROUGHOUT / ESU R: 0.285 / ESU R Free: 0.237 Details: Hydrogens have been added in their riding positions
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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 BULK SOLVENT | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 60.235 Å2
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Refinement step | Cycle: LAST / Resolution: 2.119→19.768 Å
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Refine LS restraints |
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LS refinement shell | Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20
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