+Open data
-Basic information
Entry | Database: PDB / ID: 6tia | ||||||
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Title | IRAK4 IN COMPLEX WITH inhibitor | ||||||
Components | Interleukin-1 receptor-associated kinase 4IRAK4 | ||||||
Keywords | SIGNALING PROTEIN / IRAK4 / kinase / inhibitor / cancer | ||||||
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 / MyD88-dependent toll-like receptor signaling pathway / interleukin-1-mediated 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 / phosphorylation / 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 / cytosol / cytoplasm Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.52 Å | ||||||
Authors | Xue, Y. / Aagaard, A. / Degorce, S.L. | ||||||
Citation | Journal: Bioorg.Med.Chem. / Year: 2020 Title: Improving metabolic stability and removing aldehyde oxidase liability in a 5-azaquinazoline series of IRAK4 inhibitors. Authors: Degorce, S.L. / Aagaard, A. / Anjum, R. / Cumming, I.A. / Diene, C.R. / Fallan, C. / Johnson, T. / Leuchowius, K.J. / Orton, A.L. / Pearson, S. / Robb, G.R. / Rosen, A. / Scarfe, G.B. / ...Authors: Degorce, S.L. / Aagaard, A. / Anjum, R. / Cumming, I.A. / Diene, C.R. / Fallan, C. / Johnson, T. / Leuchowius, K.J. / Orton, A.L. / Pearson, S. / Robb, G.R. / Rosen, A. / Scarfe, G.B. / Scott, J.S. / Smith, J.M. / Steward, O.R. / Terstiege, I. / Tucker, M.J. / Turner, P. / Wilkinson, S.D. / Wrigley, G.L. / Xue, Y. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 6tia.cif.gz | 139.7 KB | Display | PDBx/mmCIF format |
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PDB format | pdb6tia.ent.gz | 109.8 KB | Display | PDB format |
PDBx/mmJSON format | 6tia.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/ti/6tia ftp://data.pdbj.org/pub/pdb/validation_reports/ti/6tia | HTTPS FTP |
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-Related structure data
-Links
-Assembly
Deposited unit |
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1 |
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2 |
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Unit cell |
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-Components
#1: Protein | Mass: 34635.008 Da / Num. of mol.: 2 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 | ChemComp-ND2 / #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: 2.58 Å3/Da / Density % sol: 52.39 % |
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Crystal grow | Temperature: 298 K / Method: vapor diffusion, hanging drop Details: 2.7 M AMS 0.1 M Hepes pH 7.1-7.7 Protein Buffer: 50mM HEPES pH 7.5, 300 mM NaCl, 0,02% OG, 1 mM TCEP, 10% Glycerol |
-Data collection
Diffraction | Mean temperature: 100 K / Serial crystal experiment: N | ||||||||||||||||||||||||||||||
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Diffraction source | Source: SYNCHROTRON / Site: ESRF / Beamline: ID30B / Wavelength: 0.976 Å | ||||||||||||||||||||||||||||||
Detector | Type: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 7, 2017 | ||||||||||||||||||||||||||||||
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray | ||||||||||||||||||||||||||||||
Radiation wavelength | Wavelength: 0.976 Å / Relative weight: 1 | ||||||||||||||||||||||||||||||
Reflection | Resolution: 2.52→76.33 Å / Num. obs: 23542 / % possible obs: 93.7 % / Redundancy: 6.3 % / Biso Wilson estimate: 76.21 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.079 / Rpim(I) all: 0.034 / Rrim(I) all: 0.086 / Net I/σ(I): 16 / Num. measured all: 148380 / Scaling rejects: 43 | ||||||||||||||||||||||||||||||
Reflection shell | Diffraction-ID: 1
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-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: internal starting model Resolution: 2.52→76.33 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.901 / SU R Cruickshank DPI: 0.693 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.839 / SU Rfree Blow DPI: 0.313 / SU Rfree Cruickshank DPI: 0.311 Details: Please note that INH C1 & INH C2 are the two bound in the respective ATP pockets. The rest of ligand models (INH C3 to C10) were built to account for the residual electron density outside of ...Details: Please note that INH C1 & INH C2 are the two bound in the respective ATP pockets. The rest of ligand models (INH C3 to C10) were built to account for the residual electron density outside of the protein, interpreted as being involved in the packing interactions in the crystal (as stacking layers between protein molecules).
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Displacement parameters | Biso max: 173.38 Å2 / Biso mean: 75.5 Å2 / Biso min: 24.65 Å2
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Refine analyze | Luzzati coordinate error obs: 0.37 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: final / Resolution: 2.52→76.33 Å
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Refine LS restraints |
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LS refinement shell | Resolution: 2.52→2.53 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
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