+Open data
-Basic information
Entry | Database: PDB / ID: 4d0x | ||||||
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Title | Pyrrole-3-carboxamides as potent and selective JAK2 inhibitors | ||||||
Components | TYROSINE-PROTEIN KINASE JAK2 | ||||||
Keywords | TRANSFERASE / DRUG DISCOVERY / PROTEIN KINASE INHIBITORS / STRUCTURE-ACTIVITY RELATIONSHIP / POLYCYTHEMIA VERA / 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 / : / 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 / erythropoietin-mediated signaling pathway ...interleukin-35-mediated signaling pathway / nuclear receptor-mediated mineralocorticoid signaling pathway / histone H3Y41 kinase activity / : / 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 / erythropoietin-mediated signaling pathway / granulocyte macrophage colony-stimulating factor receptor complex / granulocyte-macrophage colony-stimulating factor signaling pathway / Signaling by Erythropoietin / collagen-activated signaling pathway / interleukin-23-mediated signaling pathway / interleukin-12 receptor binding / Erythropoietin activates STAT5 / response to interleukin-12 / interleukin-5-mediated signaling pathway / 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 platelet aggregation / positive regulation of MHC class II biosynthetic process / Interleukin-23 signaling / positive regulation of T-helper 17 type immune response / interleukin-12-mediated signaling pathway / acetylcholine receptor binding / positive regulation of platelet activation / type 1 angiotensin receptor binding / positive regulation of NK T cell proliferation / interleukin-3-mediated signaling pathway / cellular response to interleukin-3 / regulation of nitric oxide biosynthetic process / Signaling by Leptin / Interleukin-12 signaling / Interleukin-27 signaling / IL-6-type cytokine receptor ligand interactions / Interleukin-35 Signalling / positive regulation of signaling receptor activity / 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 / negative regulation of cardiac muscle cell apoptotic process / intrinsic apoptotic signaling pathway in response to oxidative stress / peptide hormone receptor binding / extrinsic component of plasma membrane / Interleukin-20 family signaling / IFNG signaling activates MAPKs / negative regulation of cell-cell adhesion / Interleukin-6 signaling / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / interleukin-6-mediated signaling pathway / enzyme-linked receptor protein signaling pathway / Prolactin receptor signaling / MAPK3 (ERK1) activation / response to amine / negative regulation of DNA binding / positive regulation of interleukin-17 production / extrinsic component of cytoplasmic side of plasma membrane / positive regulation of nitric-oxide synthase biosynthetic process / mesoderm development / MAPK1 (ERK2) activation / 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 / response to tumor necrosis factor / type II interferon-mediated signaling pathway / growth hormone receptor signaling pathway via JAK-STAT / Interleukin receptor SHC signaling / phosphatidylinositol 3-kinase binding / Regulation of IFNG signaling / positive regulation of tyrosine phosphorylation of STAT protein / Erythropoietin activates RAS / Signaling by CSF3 (G-CSF) / positive regulation of T cell proliferation / Growth hormone receptor signaling / extrinsic apoptotic signaling pathway / positive regulation of vascular associated smooth muscle cell proliferation / tumor necrosis factor-mediated signaling pathway / actin filament polymerization / post-translational protein modification / SH2 domain binding / cellular response to dexamethasone stimulus / erythrocyte differentiation / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / positive regulation of interleukin-1 beta production / endosome lumen / positive regulation of cell differentiation Similarity search - Function | ||||||
Biological species | HOMO SAPIENS (human) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.82 Å | ||||||
Authors | Canevari, G. / Fasolini, M. / Bertrand, J. / Brasca, M.G. / Nesi, M. / Avanzi, N. / Ballinari, D. / Bandiera, T. / Bindi, S. / Carenzi, D. ...Canevari, G. / Fasolini, M. / Bertrand, J. / Brasca, M.G. / Nesi, M. / Avanzi, N. / Ballinari, D. / Bandiera, T. / Bindi, S. / Carenzi, D. / Casero, D. / Ceriani, L. / Ciomei, M. / Cirla, A. / Colombo, M. / Cribioli, S. / Cristiani, C. / Della Vedova, F. / Fachin, G. / Felder, E.R. / Galvani, A. / Isacchi, A. / Mirizzi, D. / Motto, I. / Panzeri, A. / Pesenti, E. / Vianello, P. / Gnocchi, P. / Donati, D. | ||||||
Citation | Journal: Bioorg.Med.Chem. / Year: 2014 Title: Pyrrole-3-Carboxamides as Potent and Selective Jak2 Inhibitors. Authors: Brasca, M.G. / Nesi, M. / Avanzi, N. / Ballinari, D. / Bandiera, T. / Bertrand, J. / Bindi, S. / Canevari, G. / Carenzi, D. / Casero, D. / Ceriani, L. / Ciomei, M. / Cirla, A. / Colombo, M. ...Authors: Brasca, M.G. / Nesi, M. / Avanzi, N. / Ballinari, D. / Bandiera, T. / Bertrand, J. / Bindi, S. / Canevari, G. / Carenzi, D. / Casero, D. / Ceriani, L. / Ciomei, M. / Cirla, A. / Colombo, M. / Cribioli, S. / Cristiani, C. / Della Vedova, F. / Fachin, G. / Fasolini, M. / Felder, E.R. / Galvani, A. / Isacchi, A. / Mirizzi, D. / Motto, I. / Panzeri, A. / Pesenti, E. / Vianello, P. / Gnocchi, P. / Donati, D. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 4d0x.cif.gz | 83.1 KB | Display | PDBx/mmCIF format |
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PDB format | pdb4d0x.ent.gz | 60.2 KB | Display | PDB format |
PDBx/mmJSON format | 4d0x.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 4d0x_validation.pdf.gz | 804.7 KB | Display | wwPDB validaton report |
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Full document | 4d0x_full_validation.pdf.gz | 809.9 KB | Display | |
Data in XML | 4d0x_validation.xml.gz | 16.5 KB | Display | |
Data in CIF | 4d0x_validation.cif.gz | 23.7 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/d0/4d0x ftp://data.pdbj.org/pub/pdb/validation_reports/d0/4d0x | HTTPS FTP |
-Related structure data
Related structure data | 4d0wC 4d1sC 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: 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-953 / |
#3: Chemical | ChemComp-GOL / |
#4: 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 % / Description: NONE |
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Crystal grow | Temperature: 293 K / Method: vapor diffusion / pH: 7 Details: 1.5-2.2 M SODIUM MALONATE PH 7 VAPOUR DIFFUSION 293 K |
-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: 1.82→100 Å / % possible obs: 99.8 % / Observed criterion σ(I): 0 / Redundancy: 6.26 % / Rmerge(I) obs: 0.06 / Net I/σ(I): 17.73 |
Reflection shell | Resolution: 1.82→1.95 Å / Redundancy: 6.3 % / Rmerge(I) obs: 0.5 / Mean I/σ(I) obs: 3.31 / % possible all: 99.8 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: PDB ENTRY 2B7A Resolution: 1.82→68.68 Å / Cor.coef. Fo:Fc: 0.968 / Cor.coef. Fo:Fc free: 0.941 / SU B: 2.604 / SU ML: 0.081 / Cross valid method: THROUGHOUT / ESU R: 0.121 / ESU R Free: 0.127 / 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: 28.249 Å2
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Refinement step | Cycle: LAST / Resolution: 1.82→68.68 Å
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Refine LS restraints |
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