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Yorodumi- PDB-4iva: JAK2 kinase (JH1 domain) in complex with the inhibitor TRANS-4-[(... -
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-Basic information
Entry | Database: PDB / ID: 4iva | ||||||
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Title | JAK2 kinase (JH1 domain) in complex with the inhibitor TRANS-4-[(8AS)-2-[(1R)-1-HYDROXYETHYL]IMIDAZO[4,5-D]PYRROLO[2,3-B]PYRIDIN-1(8AH)-YL]CYCLOHEXANECARBONITRILE | ||||||
Components | Tyrosine-protein kinase JAK2 | ||||||
Keywords | TRANSFERASE/TRANSFERASE INHIBITOR / PROTEIN KINASE / PHOSPHOTRANSFER / TRANSFERASE-TRANSFERASE INHIBITOR COMPLEX | ||||||
Function / homology | Function and homology information interleukin-35-mediated signaling pathway / intracellular mineralocorticoid receptor 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 / Signaling by Erythropoietin ...interleukin-35-mediated signaling pathway / intracellular mineralocorticoid receptor 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 / Signaling by Erythropoietin / granulocyte macrophage colony-stimulating factor receptor complex / granulocyte-macrophage colony-stimulating factor signaling pathway / interleukin-12 receptor binding / post-embryonic hemopoiesis / collagen-activated signaling pathway / Erythropoietin activates STAT5 / Erythropoietin activates Phospholipase C gamma (PLCG) / interleukin-5-mediated signaling pathway / response to interleukin-12 / positive regulation of leukocyte proliferation / activation of Janus kinase activity / interleukin-12 receptor complex / interleukin-23 receptor complex / positive regulation of platelet aggregation / tyrosine phosphorylation of STAT protein / Interleukin-23 signaling / positive regulation of MHC class II biosynthetic process / positive regulation of platelet activation / positive regulation of T-helper 17 type immune response / type 1 angiotensin receptor binding / positive regulation of NK T cell proliferation / interleukin-12-mediated signaling pathway / interleukin-3-mediated signaling pathway / regulation of nitric oxide biosynthetic process / acetylcholine receptor binding / cellular response to interleukin-3 / Signaling by Leptin / Interleukin-12 signaling / positive regulation of signaling receptor activity / Interleukin-35 Signalling / Interleukin-27 signaling / IL-6-type cytokine receptor ligand interactions / positive regulation of cell-substrate adhesion / response to hydroperoxide / regulation of receptor signaling pathway via JAK-STAT / growth hormone receptor binding / negative regulation of cardiac muscle cell apoptotic process / positive regulation of epithelial cell apoptotic process / axon regeneration / peptide hormone receptor binding / growth hormone receptor signaling pathway / intrinsic apoptotic signaling pathway in response to oxidative stress / IFNG signaling activates MAPKs / extrinsic component of plasma membrane / Interleukin-20 family signaling / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / Interleukin-6 signaling / enzyme-linked receptor protein signaling pathway / interleukin-6-mediated signaling pathway / negative regulation of cell-cell adhesion / Prolactin receptor signaling / positive regulation of interleukin-17 production / negative regulation of DNA binding / MAPK3 (ERK1) activation / response to amine / positive regulation of nitric-oxide synthase biosynthetic process / MAPK1 (ERK2) activation / positive regulation of natural killer cell proliferation / mesoderm development / positive regulation of SMAD protein signal transduction / cell surface receptor signaling pathway via JAK-STAT / 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 / type II interferon-mediated signaling pathway / Regulation of IFNG signaling / Erythropoietin activates RAS / Growth hormone receptor signaling / positive regulation of apoptotic signaling pathway / extrinsic apoptotic signaling pathway / Signaling by CSF3 (G-CSF) / positive regulation of tyrosine phosphorylation of STAT protein / positive regulation of vascular associated smooth muscle cell proliferation / positive regulation of T cell proliferation / tumor necrosis factor-mediated signaling pathway / actin filament polymerization / extrinsic component of cytoplasmic side of plasma membrane / SH2 domain binding / cellular response to dexamethasone stimulus / post-translational protein modification / erythrocyte differentiation / 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 Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.5 Å | ||||||
Authors | Eigenbrot, C. / Shia, S. | ||||||
Citation | Journal: J.Med.Chem. / Year: 2013 Title: Identification of C-2 Hydroxyethyl Imidazopyrrolopyridines as Potent JAK1 Inhibitors with Favorable Physicochemical Properties and High Selectivity over JAK2. Authors: Zak, M. / Hurley, C.A. / Ward, S.I. / Bergeron, P. / Barrett, K. / Balazs, M. / Blair, W.S. / Bull, R. / Chakravarty, P. / Chang, C. / Crackett, P. / Deshmukh, G. / Devoss, J. / Dragovich, P. ...Authors: Zak, M. / Hurley, C.A. / Ward, S.I. / Bergeron, P. / Barrett, K. / Balazs, M. / Blair, W.S. / Bull, R. / Chakravarty, P. / Chang, C. / Crackett, P. / Deshmukh, G. / Devoss, J. / Dragovich, P.S. / Eigenbrot, C. / Ellwood, C. / Gaines, S. / Ghilardi, N. / Gibbons, P. / Gradl, S. / Gribling, P. / Hamman, C. / Harstad, E. / Hewitt, P. / Johnson, A. / Johnson, T. / Kenny, J.R. / Koehler, M.F. / Bir Kohli, P. / Labadie, S. / Lee, W.P. / Liao, J. / Liimatta, M. / Mendonca, R. / Narukulla, R. / Pulk, R. / Reeve, A. / Savage, S. / Shia, S. / Steffek, M. / Ubhayakar, S. / van Abbema, A. / Aliagas, I. / Avitabile-Woo, B. / Xiao, Y. / Yang, J. / Kulagowski, J.J. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 4iva.cif.gz | 84 KB | Display | PDBx/mmCIF format |
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PDB format | pdb4iva.ent.gz | 60.6 KB | Display | PDB format |
PDBx/mmJSON format | 4iva.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/iv/4iva ftp://data.pdbj.org/pub/pdb/validation_reports/iv/4iva | HTTPS FTP |
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-Related structure data
Related structure data | 4ivbC 4ivcC 4ivdC 2b7aS C: citing same article (ref.) S: Starting model for refinement |
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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
#1: Protein | Mass: 35342.125 Da / Num. of mol.: 1 / Fragment: UNP residues 833-1132 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: JAK2 / Production host: Spodoptera frugiperda (fall armyworm) References: UniProt: O60674, non-specific protein-tyrosine kinase |
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#2: Chemical | ChemComp-1J5 / |
#3: 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: 2.13 Å3/Da / Density % sol: 42.34 % |
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Crystal grow | Temperature: 300 K / Method: vapor diffusion, sitting drop / pH: 6 Details: AMMONIUM SULFATE, SODIUM CITRATE, PEG 8000, pH 6, VAPOR DIFFUSION, SITTING DROP, temperature 300K |
-Data collection
Diffraction | Mean temperature: 110 K |
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Diffraction source | Source: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 1.1 Å |
Detector | Type: ADSC QUANTUM 315r / Detector: CCD / Date: Oct 16, 2010 |
Radiation | Monochromator: Si 111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 1.1 Å / Relative weight: 1 |
Reflection | Resolution: 1.5→50 Å / Num. all: 45972 / Num. obs: 45968 / % possible obs: 96.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 3.7 % / Biso Wilson estimate: 16 Å2 / Rsym value: 0.049 / Net I/σ(I): 26 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: PDB ENTRY 2B7A Resolution: 1.5→24.58 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.958 / SU B: 1.249 / SU ML: 0.047 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.078 / ESU R Free: 0.074 / Stereochemistry target values: MAXIMUM LIKELIHOOD / 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: 1.4 Å / Solvent model: MASK | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 19.21 Å2
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Refinement step | Cycle: LAST / Resolution: 1.5→24.58 Å
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Refine LS restraints |
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LS refinement shell | Resolution: 1.5→1.581 Å / Total num. of bins used: 10
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