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Yorodumi- PDB-5aep: Novel pyrrole carboxamide inhibitors of JAK2 as potential treatme... -
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-Basic information
Entry | Database: PDB / ID: 5aep | ||||||
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Title | Novel pyrrole carboxamide inhibitors of JAK2 as potential treatment of myeloproliferative disorders | ||||||
Components | TYROSINE-PROTEIN KINASE JAK2 | ||||||
Keywords | TRANSFERASE / PROTEIN KINASE / JAK2 / MYELOPROLIFERATIVE DISORDERS / TUMOUR CELL PROLIFERATION INHIBITION / ANTI-CANCER AGENTS | ||||||
Function / homology | Function and homology information 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 / Signaling by Erythropoietin / collagen-activated signaling pathway / interleukin-12 receptor binding / 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 / tyrosine phosphorylation of STAT protein / interleukin-23 receptor complex / positive regulation of MHC class II biosynthetic process / positive regulation of platelet aggregation / Interleukin-23 signaling / type 1 angiotensin receptor binding / positive regulation of T-helper 17 type immune response / positive regulation of platelet activation / acetylcholine receptor binding / positive regulation of NK T cell proliferation / interleukin-12-mediated signaling pathway / cellular response to interleukin-3 / interleukin-3-mediated signaling pathway / regulation of nitric oxide biosynthetic process / positive regulation of signaling receptor activity / Signaling by Leptin / Interleukin-12 signaling / Interleukin-27 signaling / IL-6-type cytokine receptor ligand interactions / Interleukin-35 Signalling / positive regulation of epithelial cell apoptotic process / positive regulation of natural killer cell proliferation / positive regulation of cell-substrate adhesion / regulation of receptor signaling pathway via JAK-STAT / growth hormone receptor binding / response to hydroperoxide / 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 / extrinsic component of plasma membrane / IFNG signaling activates MAPKs / 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 / negative regulation of DNA binding / positive regulation of nitric-oxide synthase biosynthetic process / response to amine / positive regulation of interleukin-17 production / extrinsic component of cytoplasmic side of plasma membrane / MAPK1 (ERK2) activation / mesoderm development / cell surface receptor signaling pathway via JAK-STAT / positive regulation of SMAD protein signal transduction / platelet-derived growth factor receptor signaling pathway / Interleukin-3, Interleukin-5 and GM-CSF signaling / insulin receptor substrate binding / growth hormone receptor signaling pathway via JAK-STAT / response to tumor necrosis factor / Interleukin receptor SHC signaling / post-translational protein modification / cellular response to dexamethasone stimulus / phosphatidylinositol 3-kinase binding / Regulation of IFNG signaling / type II interferon-mediated signaling pathway / Erythropoietin activates RAS / Growth hormone receptor signaling / extrinsic apoptotic signaling pathway / positive regulation of T cell proliferation / Signaling by CSF3 (G-CSF) / positive regulation of tyrosine phosphorylation of STAT protein / positive regulation of vascular associated smooth muscle cell proliferation / tumor necrosis factor-mediated signaling pathway / actin filament polymerization / SH2 domain binding / erythrocyte differentiation / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / positive regulation of apoptotic signaling pathway / 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: 1.95 Å | ||||||
Authors | Canevari, G. / Bertrand, J. / Brasca, M.G. / Nesi, M. / Amboldi, N. / Avanzi, N. / Bindi, S. / Casero, D. / Ciomei, M. / Colombo, N. ...Canevari, G. / Bertrand, J. / Brasca, M.G. / Nesi, M. / Amboldi, N. / Avanzi, N. / Bindi, S. / Casero, D. / Ciomei, M. / Colombo, N. / Cribioli, S. / Fachin, G. / Felder, E.R. / Galvani, A. / Isacchi, A. / Motto, I. / Panzeri, A. / Gnocchi, P. / Donati, D. | ||||||
Citation | Journal: Bioorg.Med.Chem. / Year: 2015 Title: Novel Pyrrole Carboxamide Inhibitors of Jak2 as Potential Treatment of Myeloproliferative Disorders. Authors: Brasca, M.G. / Gnocchi, P. / Nesi, M. / Amboldi, N. / Avanzi, N. / Bertrand, J. / Bindi, S. / Canevari, G. / Casero, D. / Ciomei, M. / Colombo, N. / Cribioli, S. / Fachin, G. / Felder, E.R. ...Authors: Brasca, M.G. / Gnocchi, P. / Nesi, M. / Amboldi, N. / Avanzi, N. / Bertrand, J. / Bindi, S. / Canevari, G. / Casero, D. / Ciomei, M. / Colombo, N. / Cribioli, S. / Fachin, G. / Felder, E.R. / Galvani, A. / Isacchi, A. / Motto, I. / Panzeri, A. / Donati, D. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 5aep.cif.gz | 77.9 KB | Display | PDBx/mmCIF format |
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PDB format | pdb5aep.ent.gz | 57.8 KB | Display | PDB format |
PDBx/mmJSON format | 5aep.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 5aep_validation.pdf.gz | 787.9 KB | Display | wwPDB validaton report |
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Full document | 5aep_full_validation.pdf.gz | 792.6 KB | Display | |
Data in XML | 5aep_validation.xml.gz | 15 KB | Display | |
Data in CIF | 5aep_validation.cif.gz | 21.1 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/ae/5aep ftp://data.pdbj.org/pub/pdb/validation_reports/ae/5aep | HTTPS FTP |
-Related structure data
Related structure data | 4d0wS 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: 35197.992 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN, RESIDUES 835-1132 Source method: isolated from a genetically manipulated source Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): Sf21 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) References: UniProt: O60674, non-specific protein-tyrosine kinase |
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#2: Chemical | ChemComp-QUP / |
#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: 2.29 Å3/Da / Density % sol: 46.32 % / Description: NONE |
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Crystal grow | Temperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7 Details: 1.5-2.2 M SODIUM MALONATE PH 7, HANGING DROP AT 20 DEGREES CELSIUS |
-Data collection
Diffraction | Mean temperature: 100 K |
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Diffraction source | Source: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 0.885601 |
Detector | Type: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 15, 2011 / Details: TOROIDAL MIRROR |
Radiation | Monochromator: SI(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 0.885601 Å / Relative weight: 1 |
Reflection | Resolution: 1.95→48.2 Å / Num. obs: 23732 / % possible obs: 94.4 % / Observed criterion σ(I): 0 / Redundancy: 4.7 % / Rmerge(I) obs: 0.07 / Net I/σ(I): 12.1 |
Reflection shell | Resolution: 1.95→2.05 Å / Redundancy: 4.9 % / Rmerge(I) obs: 0.38 / Mean I/σ(I) obs: 3.6 / % possible all: 95.8 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: PDB ENTRY 4D0W Resolution: 1.95→68.79 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.946 / Cross valid method: THROUGHOUT / ESU R: 0.157 / ESU R Free: 0.144 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
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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 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: LAST / Resolution: 1.95→68.79 Å
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Refine LS restraints |
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