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Yorodumi- PDB-4f09: Discovery and Optimization of C-2 Methyl Imidazo-pyrrolopyridines... -
+Open data
-Basic information
Entry | Database: PDB / ID: 4f09 | ||||||
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Title | Discovery and Optimization of C-2 Methyl Imidazo-pyrrolopyridines as Potent and Orally Bioavailable JAK1 Inhibitors with Selectivity over JAK2 | ||||||
Components | Tyrosine-protein kinase JAK2 | ||||||
Keywords | TRANSFERASE/TRANSFERASE INHIBITOR / JAK2 / kinase domain / JH1 domain / 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 / 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 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 / molecular replacement / Resolution: 2.4 Å | ||||||
Authors | Murray, J.M. | ||||||
Citation | Journal: J.Med.Chem. / Year: 2012 Title: Discovery and Optimization of C-2 Methyl Imidazopyrrolopyridines as Potent and Orally Bioavailable JAK1 Inhibitors with Selectivity over JAK2. Authors: Zak, M. / Mendonca, R. / Balazs, M. / Barrett, K. / Bergeron, P. / Blair, W.S. / Chang, C. / Deshmukh, G. / Devoss, J. / Dragovich, P.S. / Eigenbrot, C. / Ghilardi, N. / Gibbons, P. / Gradl, ...Authors: Zak, M. / Mendonca, R. / Balazs, M. / Barrett, K. / Bergeron, P. / Blair, W.S. / Chang, C. / Deshmukh, G. / Devoss, J. / Dragovich, P.S. / Eigenbrot, C. / Ghilardi, N. / Gibbons, P. / Gradl, S. / Hamman, C. / Hanan, E.J. / Harstad, E. / Hewitt, P.R. / Hurley, C.A. / Jin, T. / Johnson, A. / Johnson, T. / Kenny, J.R. / Koehler, M.F. / Bir Kohli, P. / Kulagowski, J.J. / Labadie, S. / Liao, J. / Liimatta, M. / Lin, Z. / Lupardus, P.J. / Maxey, R.J. / Murray, J.M. / Pulk, R. / Rodriguez, M. / Savage, S. / Shia, S. / Steffek, M. / Ubhayakar, S. / Ultsch, M. / van Abbema, A. / Ward, S.I. / Xiao, L. / Xiao, Y. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 4f09.cif.gz | 78 KB | Display | PDBx/mmCIF format |
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PDB format | pdb4f09.ent.gz | 56.1 KB | Display | PDB format |
PDBx/mmJSON format | 4f09.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/f0/4f09 ftp://data.pdbj.org/pub/pdb/validation_reports/f0/4f09 | HTTPS FTP |
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-Related structure data
Related structure data | 4ehzC 4ei4C 4f08C 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: 35486.254 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 kinase domain / Production host: Spodoptera frugiperda (fall armyworm) References: UniProt: O60674, non-specific protein-tyrosine kinase |
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#2: Chemical | ChemComp-JAK / |
#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: 2.22 Å3/Da / Density % sol: 44.61 % |
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Crystal grow | Temperature: 277 K / pH: 6 Details: 0.2 M ammonium acetate, 0.1M sodium citrate pH6, 20 % PEG 8000, VAPOR DIFFUSION, HANGING DROP, temperature 277K |
-Data collection
Diffraction | Mean temperature: 100 K |
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Diffraction source | Source: SYNCHROTRON / Site: SSRL / Beamline: BL7-1 / Wavelength: 0.979 |
Detector | Type: ADSC QUANTUM 315r / Detector: CCD / Date: Mar 17, 2010 |
Radiation | Protocol: SINGLE / Scattering type: x-ray |
Radiation wavelength | Wavelength: 0.979 Å / Relative weight: 1 |
Reflection | Resolution: 2.4→50 Å / Num. obs: 13267 / % possible obs: 83.2 % / Observed criterion σ(I): 0 / Redundancy: 3.1 % / Biso Wilson estimate: 18 Å2 / Rmerge(I) obs: 0.095 / Net I/σ(I): 7.9 |
Reflection shell | Resolution: 2.15→2.23 Å / Redundancy: 1.6 % / Rmerge(I) obs: 0.28 / % possible all: 33 |
-Phasing
Phasing | Method: molecular replacement |
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-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: PDB ENTRY 2B7A Resolution: 2.4→49.28 Å / Cor.coef. Fo:Fc: 0.906 / Cor.coef. Fo:Fc free: 0.828 / Occupancy max: 1 / Occupancy min: 1 / SU R Cruickshank DPI: 0.548 / Cross valid method: THROUGHOUT / σ(F): 0
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Displacement parameters | Biso mean: 25.24 Å2
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Refine analyze | Luzzati coordinate error obs: 0.27 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: LAST / Resolution: 2.4→49.28 Å
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Refine LS restraints |
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LS refinement shell | Resolution: 2.4→2.63 Å / Total num. of bins used: 6
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