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- PDB-4d0x: Pyrrole-3-carboxamides as potent and selective JAK2 inhibitors -

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Basic information

Entry
Database: PDB / ID: 4d0x
TitlePyrrole-3-carboxamides as potent and selective JAK2 inhibitors
ComponentsTYROSINE-PROTEIN KINASE JAK2
KeywordsTRANSFERASE / DRUG DISCOVERY / PROTEIN KINASE INHIBITORS / STRUCTURE-ACTIVITY RELATIONSHIP / POLYCYTHEMIA VERA / TUMOUR CELL PROLIFERATION INHIBITION / ANTI-CANCER AGENTS
Function / homology
Function and homology information


RMTs methylate histone arginines / Signaling by SCF-KIT / Prolactin receptor signaling / Interleukin-3, Interleukin-5 and GM-CSF signaling / RAF activation / RAF/MAP kinase cascade / Interleukin-4 and Interleukin-13 signaling / IL-6-type cytokine receptor ligand interactions / Interleukin-6 signaling / MAPK3 (ERK1) activation ...RMTs methylate histone arginines / Signaling by SCF-KIT / Prolactin receptor signaling / Interleukin-3, Interleukin-5 and GM-CSF signaling / RAF activation / RAF/MAP kinase cascade / Interleukin-4 and Interleukin-13 signaling / IL-6-type cytokine receptor ligand interactions / Interleukin-6 signaling / MAPK3 (ERK1) activation / MAPK1 (ERK2) activation / Signaling by Leptin / Interleukin-23 signaling / Cyclin D associated events in G1 / Interleukin-35 Signalling / Interleukin-20 family signaling / Interleukin-27 signaling / Regulation of IFNG signaling / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / Interferon gamma signaling / Erythropoietin activates Phospholipase C gamma (PLCG) / Erythropoietin activates STAT5 / Interleukin-12 signaling / Erythropoietin activates RAS / Signaling by Erythropoietin / Signaling by BRAF and RAF fusions / Signaling by moderate kinase activity BRAF mutants / Signaling by RAS mutants / Interleukin receptor SHC signaling / Growth hormone receptor signaling / Factors involved in megakaryocyte development and platelet production / Paradoxical activation of RAF signaling by kinase inactive BRAF / mineralocorticoid receptor signaling pathway / histone H3-Y41 phosphorylation / histone kinase activity (H3-Y41 specific) / positive regulation of growth hormone receptor signaling pathway / mammary gland epithelium development / positive regulation of growth factor dependent skeletal muscle satellite cell proliferation / interleukin-12 receptor binding / response to interleukin-12 / positive regulation of epithelial cell apoptotic process / interleukin-35-mediated signaling pathway / interleukin-23-mediated signaling pathway / tyrosine phosphorylation of STAT protein / activation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway / regulation of nitric oxide biosynthetic process / type 1 angiotensin receptor binding / activation of Janus kinase activity / positive regulation of receptor biosynthetic process / positive regulation of MHC class II biosynthetic process / positive regulation of cell-substrate adhesion / interleukin-27-mediated signaling pathway / growth hormone receptor binding / response to hydroperoxide / regulation of receptor signaling pathway via JAK-STAT / receptor signaling pathway via JAK-STAT / regulation of interferon-gamma-mediated signaling pathway / peptide hormone receptor binding / intrinsic apoptotic signaling pathway in response to oxidative stress / negative regulation of cardiac muscle cell apoptotic process / postsynapse to nucleus signaling pathway / positive regulation of cell activation / growth hormone receptor signaling pathway / enzyme linked receptor protein signaling pathway / axon regeneration / interleukin-6-mediated signaling pathway / negative regulation of cell-cell adhesion / platelet-derived growth factor receptor signaling pathway / positive regulation of interleukin-1 beta biosynthetic process / acetylcholine receptor binding / mesoderm development / positive regulation of nitric-oxide synthase biosynthetic process / insulin receptor substrate binding / positive regulation of phosphoprotein phosphatase activity / response to tumor necrosis factor / growth hormone receptor signaling pathway via JAK-STAT / positive regulation of tumor necrosis factor biosynthetic process / positive regulation of insulin secretion / negative regulation of DNA binding / negative regulation of heart contraction / erythrocyte differentiation / extrinsic apoptotic signaling pathway / positive regulation of Ras protein signal transduction / actin filament polymerization / phosphatidylinositol 3-kinase binding / positive regulation of vascular smooth muscle cell proliferation / activation of MAPKK activity / positive regulation of tyrosine phosphorylation of STAT protein / tumor necrosis factor-mediated signaling pathway / positive regulation of tumor necrosis factor production / endosome lumen / microglial cell activation / SH2 domain binding / positive regulation of cell differentiation / positive regulation of DNA binding / interleukin-12-mediated signaling pathway / positive regulation of inflammatory response / caveola / nuclear matrix / non-specific protein-tyrosine kinase
Jak1, pleckstrin homology-like domain / Protein kinase-like domain superfamily / Tyrosine-protein kinase, non-receptor Jak/Tyk2 / Protein kinase, ATP binding site / Band 4.1 domain / Tyrosine-protein kinase, catalytic domain / Tyrosine-protein kinase, non-receptor Jak2 / Janus kinase 2, pseudokinase domain / Janus kinase 2, catalytic domain / Tyrosine-protein kinase, active site ...Jak1, pleckstrin homology-like domain / Protein kinase-like domain superfamily / Tyrosine-protein kinase, non-receptor Jak/Tyk2 / Protein kinase, ATP binding site / Band 4.1 domain / Tyrosine-protein kinase, catalytic domain / Tyrosine-protein kinase, non-receptor Jak2 / Janus kinase 2, pseudokinase domain / Janus kinase 2, catalytic domain / Tyrosine-protein kinase, active site / Serine-threonine/tyrosine-protein kinase, catalytic domain / Src homology 2 (SH2) domain profile. / Jak1 pleckstrin homology-like domain / FERM F2 acyl-CoA binding protein-like domain / FERM F1 ubiquitin-like domain / Protein tyrosine kinase / Protein kinases ATP-binding region signature. / Tyrosine protein kinases specific active-site signature. / Protein kinase domain profile. / SH2 domain / FERM domain profile. / FERM domain / Protein kinase domain / SH2 domain / Tyrosine-protein kinase JAK2, SH2 domain / SH2 domain superfamily / FERM superfamily, second domain / JAK2, FERM domain C-lobe / JAK, FERM F2 lobe domain / FERM F1 lobe ubiquitin-like domain
Tyrosine-protein kinase JAK2
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.82 Å
AuthorsCanevari, 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.
CitationJournal: 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. / 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.
Validation Report
SummaryFull reportAbout validation report
History
DepositionApr 30, 2014Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 23, 2014Provider: repository / Type: Initial release
Revision 1.1Sep 10, 2014Group: Database references
Revision 1.2Sep 27, 2017Group: Data collection / Category: diffrn_detector / Item: _diffrn_detector.type
Revision 1.3Mar 6, 2019Group: Data collection / Derived calculations / Experimental preparation
Category: database_PDB_rev / database_PDB_rev_record ...database_PDB_rev / database_PDB_rev_record / exptl_crystal_grow / struct_conn
Item: _exptl_crystal_grow.method / _exptl_crystal_grow.temp / _struct_conn.pdbx_leaving_atom_flag
Revision 1.4Apr 24, 2019Group: Data collection / Source and taxonomy / Category: entity_src_gen / Item: _entity_src_gen.pdbx_host_org_cell_line

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: TYROSINE-PROTEIN KINASE JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,6723
Polymers35,1981
Non-polymers4742
Water4,053225
1


TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
γ
α
β
Length a, b, c (Å)93.070, 101.760, 67.710
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221

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Components

#1: Protein/peptide TYROSINE-PROTEIN KINASE JAK2 / JANUS KINASE 2 / JAK-2


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
#2: Chemical ChemComp-953 / 5-(2-aminopyrimidin-4-yl)-2-[2-chloro-5-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide


Mass: 381.740 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H11ClF3N5O
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3 / Glycerol
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 225 / Source method: isolated from a natural source / Formula: H2O / Water

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.29 Å3/Da / Density % sol: 46 % / Description: NONE
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 7
Details: 1.5-2.2 M SODIUM MALONATE PH 7 VAPOUR DIFFUSION 293 K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 0.885601
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 15, 2011 / Details: TOROIDAL MIRROR
RadiationMonochromator: SI(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.885601 Å / Relative weight: 1
ReflectionResolution: 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 shellResolution: 1.82→1.95 Å / Redundancy: 6.3 % / Rmerge(I) obs: 0.5 / Mean I/σ(I) obs: 3.31 / % possible all: 99.8

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Processing

Software
NameVersionClassification
REFMAC5.6.0117refinement
XDSdata reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod 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.
RfactorNum. reflection% reflectionSelection details
Rfree0.21868 1477 5.1 %RANDOM
Rwork0.16334 ---
Obs0.16614 27655 99.84 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 28.249 Å2
Baniso -1Baniso -2Baniso -3
1--1.11 Å20 Å20 Å2
2--1.25 Å20 Å2
3----0.14 Å2
Refinement stepCycle: LAST / Resolution: 1.82→68.68 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2426 0 32 225 2683
Refine LS restraints

Refinement-ID: X-RAY DIFFRACTION

TypeDev idealDev ideal targetNumber
r_bond_refined_d0.0220.022534
r_bond_other_d
r_angle_refined_deg2.1061.9933424
r_angle_other_deg
r_dihedral_angle_1_deg6.1155300
r_dihedral_angle_2_deg38.62324.016127
r_dihedral_angle_3_deg16.01215470
r_dihedral_angle_4_deg16.1481520
r_chiral_restr0.1460.2356
r_gen_planes_refined0.0120.0211931
r_gen_planes_other
r_nbd_refined
r_nbd_other
r_nbtor_refined
r_nbtor_other
r_xyhbond_nbd_refined
r_xyhbond_nbd_other
r_metal_ion_refined
r_metal_ion_other
r_symmetry_vdw_refined
r_symmetry_vdw_other
r_symmetry_hbond_refined
r_symmetry_hbond_other
r_symmetry_metal_ion_refined
r_symmetry_metal_ion_other
r_mcbond_it
r_mcbond_other
r_mcangle_it
r_mcangle_other
r_scbond_it
r_scbond_other
r_scangle_it
r_scangle_other
r_long_range_B_refined
r_long_range_B_other
r_rigid_bond_restr
r_sphericity_free
r_sphericity_bonded
LS refinement shellResolution: 1.82→1.867 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.299 94 -
Rwork0.239 1876 -
Obs--99.75 %

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