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Yorodumi- PDB-3lpb: Crystal structure of Jak2 complexed with a potent 2,8-diaryl-quin... -
+Open data
-Basic information
Entry | Database: PDB / ID: 3lpb | ||||||
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Title | Crystal structure of Jak2 complexed with a potent 2,8-diaryl-quinoxaline inhibitor | ||||||
Components | Tyrosine-protein kinase JAK2 | ||||||
Keywords | TRANSFERASE / Small molecule inhibitor / ATP site kinase inhibitor / Novartis product NVP-BLU040 / ATP-binding / Chromosomal rearrangement / Disease mutation / Kinase / Membrane / Nucleotide-binding / Phosphoprotein / Polymorphism / Proto-oncogene / SH2 domain / Tyrosine-protein kinase | ||||||
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 / interleukin-12 receptor complex / activation of Janus kinase activity / 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 / growth hormone receptor signaling pathway / peptide hormone receptor binding / 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 / mesoderm development / positive regulation of natural killer cell proliferation / 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 / extrinsic apoptotic signaling pathway / positive regulation of 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 / extrinsic component of cytoplasmic side of plasma membrane / actin filament polymerization / 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: 2 Å | ||||||
Authors | Tavares, G.A. / Pissot-Soldermann, C. / Gerspacher, M. / Furet, P. / Kroemer, M. | ||||||
Citation | Journal: Bioorg.Med.Chem.Lett. / Year: 2010 Title: Discovery and SAR of potent, orally available 2,8-diaryl-quinoxalines as a new class of JAK2 inhibitors Authors: Pissot-Soldermann, C. / Gerspacher, M. / Furet, P. / Gaul, C. / Holzer, P. / McCarthy, C. / Radimerski, T. / Regnier, C.H. / Baffert, F. / Drueckes, P. / Tavares, G.A. / Vangrevelinghe, E. / ...Authors: Pissot-Soldermann, C. / Gerspacher, M. / Furet, P. / Gaul, C. / Holzer, P. / McCarthy, C. / Radimerski, T. / Regnier, C.H. / Baffert, F. / Drueckes, P. / Tavares, G.A. / Vangrevelinghe, E. / Blasco, F. / Ottaviani, G. / Ossola, F. / Scesa, J. / Reetz, J. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 3lpb.cif.gz | 136.8 KB | Display | PDBx/mmCIF format |
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PDB format | pdb3lpb.ent.gz | 105.9 KB | Display | PDB format |
PDBx/mmJSON format | 3lpb.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/lp/3lpb ftp://data.pdbj.org/pub/pdb/validation_reports/lp/3lpb | HTTPS FTP |
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-Related structure data
Related structure data | 2b7aS 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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2 |
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Unit cell |
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-Components
#1: Protein | Mass: 34722.484 Da / Num. of mol.: 2 / Fragment: Kinase domain Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Plasmid: PACG2TTEV / Cell line (production host): SF9DE / Production host: Spodoptera frugiperda (fall armyworm) References: UniProt: O60674, non-specific protein-tyrosine kinase #2: Chemical | #3: Water | ChemComp-HOH / | |
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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: 3.21 Å3/Da / Density % sol: 61.71 % |
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Crystal grow | Temperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.2 Details: 30% PEG4000, 0.1M AMMONIUM SULFATE, 0.1M NA CITRATE, pH 6.2, VAPOR DIFFUSION, HANGING DROP, temperature 298K |
-Data collection
Diffraction | Mean temperature: 100 K |
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Diffraction source | Source: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.9999 Å |
Detector | Type: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Oct 21, 2006 / Details: SAGITALLY FOCUSED SI(III) |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 0.9999 Å / Relative weight: 1 |
Reflection | Resolution: 2→79.49 Å / Num. obs: 58981 / % possible obs: 98.8 % / Redundancy: 3.32 % / Biso Wilson estimate: 36.6 Å2 / Rmerge(I) obs: 0.05 / Net I/σ(I): 15.06 |
Reflection shell | Resolution: 2→2.06 Å / Redundancy: 2.87 % / Rmerge(I) obs: 0.347 / Mean I/σ(I) obs: 3.3 / Num. unique all: 4533 / % possible all: 90.1 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: 2b7a Resolution: 2→79.47 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.949 / SU B: 3.225 / SU ML: 0.089 / Cross valid method: THROUGHOUT / ESU R: 0.133 / ESU R Free: 0.125 / 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: 1.2 Å / Solvent model: MASK | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 33.946 Å2
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Refinement step | Cycle: LAST / Resolution: 2→79.47 Å
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Refine LS restraints |
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LS refinement shell | Resolution: 2→2.052 Å / Total num. of bins used: 20
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