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- PDB-5tq6: Design and Synthesis of a pan-JAK Kinase Inhibitor Clinical Candi... -
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Basic information
Entry | Database: PDB / ID: 5tq6 | ||||||
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Title | Design and Synthesis of a pan-JAK Kinase Inhibitor Clinical Candidate (PF-06263276) Suitable for Inhaled and Topical Delivery for the Treatment of Inflammatory Diseases of the Lungs and Skin | ||||||
![]() | Tyrosine-protein kinase JAK2 | ||||||
![]() | Transferase/Transferase Inhibitor / Kinase / Inflammation / Jak Inhibitor / Transferase-Transferase Inhibitor complex | ||||||
Function / homology | ![]() interleukin-35-mediated signaling pathway / nuclear receptor-mediated mineralocorticoid signaling pathway / histone H3Y41 kinase activity / activation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway / positive regulation of growth factor dependent skeletal muscle satellite cell proliferation / symbiont-induced defense-related programmed cell death / mammary gland epithelium development / regulation of postsynapse to nucleus signaling pathway / positive regulation of growth hormone receptor signaling pathway / granulocyte macrophage colony-stimulating factor receptor complex ...interleukin-35-mediated signaling pathway / nuclear receptor-mediated mineralocorticoid signaling pathway / histone H3Y41 kinase activity / activation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway / positive regulation of growth factor dependent skeletal muscle satellite cell proliferation / symbiont-induced defense-related programmed cell death / mammary gland epithelium development / regulation of postsynapse to nucleus signaling pathway / positive regulation of growth hormone receptor signaling pathway / granulocyte macrophage colony-stimulating factor receptor complex / granulocyte-macrophage colony-stimulating factor signaling pathway / interleukin-12 receptor binding / Signaling by Erythropoietin / collagen-activated signaling pathway / Erythropoietin activates STAT5 / interleukin-5-mediated signaling pathway / response to interleukin-12 / Erythropoietin activates Phospholipase C gamma (PLCG) / positive regulation of leukocyte proliferation / post-embryonic hemopoiesis / interleukin-12 receptor complex / activation of Janus kinase activity / interleukin-23 receptor complex / tyrosine phosphorylation of STAT protein / Interleukin-23 signaling / positive regulation of MHC class II biosynthetic process / positive regulation of platelet aggregation / positive regulation of T-helper 17 type immune response / type 1 angiotensin receptor binding / positive regulation of platelet activation / positive regulation of NK T cell proliferation / interleukin-12-mediated signaling pathway / acetylcholine receptor binding / cellular response to interleukin-3 / interleukin-3-mediated signaling pathway / Signaling by Leptin / regulation of nitric oxide biosynthetic process / positive regulation of signaling receptor activity / Interleukin-12 signaling / Interleukin-35 Signalling / Interleukin-27 signaling / IL-6-type cytokine receptor ligand interactions / positive regulation of epithelial cell apoptotic process / positive regulation of natural killer cell proliferation / response to hydroperoxide / positive regulation of cell-substrate adhesion / regulation of receptor signaling pathway via JAK-STAT / growth hormone receptor binding / axon regeneration / growth hormone receptor signaling pathway / peptide hormone receptor binding / negative regulation of cardiac muscle cell apoptotic process / intrinsic apoptotic signaling pathway in response to oxidative stress / IFNG signaling activates MAPKs / extrinsic component of plasma membrane / Interleukin-20 family signaling / interleukin-6-mediated signaling pathway / negative regulation of cell-cell adhesion / Interleukin-6 signaling / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / enzyme-linked receptor protein signaling pathway / Prolactin receptor signaling / MAPK3 (ERK1) activation / positive regulation of interleukin-17 production / response to amine / negative regulation of DNA binding / positive regulation of nitric-oxide synthase biosynthetic process / MAPK1 (ERK2) activation / cell surface receptor signaling pathway via JAK-STAT / mesoderm development / positive regulation of SMAD protein signal transduction / platelet-derived growth factor receptor signaling pathway / insulin receptor substrate binding / Interleukin-3, Interleukin-5 and GM-CSF signaling / growth hormone receptor signaling pathway via JAK-STAT / response to tumor necrosis factor / Interleukin receptor SHC signaling / phosphatidylinositol 3-kinase binding / Regulation of IFNG signaling / type II interferon-mediated signaling pathway / Erythropoietin activates RAS / Growth hormone receptor signaling / positive regulation of T cell proliferation / extrinsic apoptotic signaling pathway / Signaling by CSF3 (G-CSF) / positive regulation of tyrosine phosphorylation of STAT protein / extrinsic component of cytoplasmic side of plasma membrane / positive regulation of vascular associated smooth muscle cell proliferation / tumor necrosis factor-mediated signaling pathway / actin filament polymerization / SH2 domain binding / cellular response to dexamethasone stimulus / erythrocyte differentiation / post-translational protein modification / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / positive regulation of interleukin-1 beta production / caveola / endosome lumen / positive regulation of cell differentiation / positive regulation of apoptotic signaling pathway Similarity search - Function | ||||||
Biological species | ![]() | ||||||
Method | ![]() ![]() ![]() | ||||||
![]() | Chrencik, J. / Jones, P. | ||||||
![]() | ![]() Title: Design and Synthesis of a Pan-Janus Kinase Inhibitor Clinical Candidate (PF-06263276) Suitable for Inhaled and Topical Delivery for the Treatment of Inflammatory Diseases of the Lungs and Skin. Authors: Jones, P. / Storer, R.I. / Sabnis, Y.A. / Wakenhut, F.M. / Whitlock, G.A. / England, K.S. / Mukaiyama, T. / Dehnhardt, C.M. / Coe, J.W. / Kortum, S.W. / Chrencik, J.E. / Brown, D.G. / Jones, ...Authors: Jones, P. / Storer, R.I. / Sabnis, Y.A. / Wakenhut, F.M. / Whitlock, G.A. / England, K.S. / Mukaiyama, T. / Dehnhardt, C.M. / Coe, J.W. / Kortum, S.W. / Chrencik, J.E. / Brown, D.G. / Jones, R.M. / Murphy, J.R. / Yeoh, T. / Morgan, P. / Kilty, I. | ||||||
History |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 133.7 KB | Display | ![]() |
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PDB format | ![]() | 102 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
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-Validation report
Summary document | ![]() | 992.8 KB | Display | ![]() |
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Full document | ![]() | 1005.6 KB | Display | |
Data in XML | ![]() | 14.4 KB | Display | |
Data in CIF | ![]() | 21.7 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 5tq3C ![]() 5tq4C ![]() 5tq5C ![]() 5tq7C ![]() 5tq8C ![]() 3tjcS C: citing same article ( S: Starting model for refinement |
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Similar structure data |
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Links
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Assembly
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Unit cell |
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Components
#1: Protein | Mass: 35906.684 Da / Num. of mol.: 2 / Fragment: UNP residues 837-1132 / Mutation: M1073S, F1076T Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() References: UniProt: O60674, non-specific protein-tyrosine kinase #2: Chemical | #3: Water | ChemComp-HOH / | |
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-Experimental details
-Experiment
Experiment | Method: ![]() |
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Sample preparation
Crystal | Density Matthews: 2.32 Å3/Da / Density % sol: 47.08 % |
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Crystal grow | Temperature: 293 K / Method: vapor diffusion Details: 0.1 M Hepes, pH 7.5, 0.1 M sodium acetate, 30% PEG3350 |
-Data collection
Diffraction | Mean temperature: 100 K |
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Diffraction source | Source: ![]() ![]() ![]() |
Detector | Type: ADSC QUANTUM 210 / Detector: CCD / Date: Mar 1, 2007 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 1 Å / Relative weight: 1 |
Reflection | Resolution: 2.06→47.54 Å / Num. obs: 37639 / % possible obs: 93 % / Redundancy: 3.6 % / Rmerge(I) obs: 0.07 / Net I/σ(I): 11.4 |
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Processing
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Refinement | Method to determine structure: ![]() Starting model: 3TJC Resolution: 2.06→47.54 Å / Cor.coef. Fo:Fc: 0.864 / Cor.coef. Fo:Fc free: 0.82 / SU B: 5.31 / SU ML: 0.15 / Cross valid method: THROUGHOUT / ESU R: 0.302 / ESU R Free: 0.229 / Details: HYDROGENS HAVE BEEN ADDED IN THE 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 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 19.884 Å2
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Refinement step | Cycle: 1 / Resolution: 2.06→47.54 Å
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Refine LS restraints |
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