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- PDB-5l3a: Fragment-based discovery of 6-arylindazole JAK inhibitors -

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Basic information

Entry
Database: PDB / ID: 5l3a
TitleFragment-based discovery of 6-arylindazole JAK inhibitors
ComponentsTyrosine-protein kinase JAK2
KeywordsTRANSFERASE / Double F mutant
Function / homology
Function and homology information


interleukin-35-mediated signaling pathway / nuclear receptor-mediated mineralocorticoid 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 / interleukin-12 receptor complex / histone H3Y41 kinase activity / interleukin-23 receptor complex ...interleukin-35-mediated signaling pathway / nuclear receptor-mediated mineralocorticoid 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 / interleukin-12 receptor complex / histone H3Y41 kinase activity / interleukin-23 receptor complex / granulocyte macrophage colony-stimulating factor receptor complex / granulocyte-macrophage colony-stimulating factor signaling pathway / thrombopoietin-mediated signaling pathway / Signaling by Erythropoietin / collagen-activated signaling pathway / interleukin-12 receptor binding / Erythropoietin activates STAT5 / interleukin-5-mediated signaling pathway / interleukin-23-mediated signaling pathway / activation of Janus kinase activity / response to interleukin-12 / Erythropoietin activates Phospholipase C gamma (PLCG) / Interleukin-23 signaling / positive regulation of leukocyte proliferation / positive regulation of T-helper 17 type immune response / interleukin-12-mediated signaling pathway / type 1 angiotensin receptor binding / positive regulation of NK T cell proliferation / post-embryonic hemopoiesis / erythropoietin-mediated signaling pathway / Interleukin-12 signaling / IL-6-type cytokine receptor ligand interactions / Interleukin-27 signaling / Interleukin-35 Signalling / positive regulation of MHC class II biosynthetic process / acetylcholine receptor binding / positive regulation of natural killer cell proliferation / positive regulation of platelet activation / growth hormone receptor binding / regulation of nitric oxide biosynthetic process / cellular response to interleukin-3 / interleukin-3-mediated signaling pathway / positive regulation of platelet aggregation / Signaling by Leptin / positive regulation of epithelial cell apoptotic process / regulation of receptor signaling pathway via JAK-STAT / positive regulation of cell-substrate adhesion / extrinsic component of cytoplasmic side of plasma membrane / axon regeneration / extrinsic component of plasma membrane / response to hydroperoxide / Interleukin-20 family signaling / growth hormone receptor signaling pathway / Interleukin-6 signaling / negative regulation of cardiac muscle cell apoptotic process / positive regulation of tyrosine phosphorylation of STAT protein / intrinsic apoptotic signaling pathway in response to oxidative stress / negative regulation of cell-cell adhesion / peptide hormone receptor binding / IFNG signaling activates MAPKs / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / MAPK3 (ERK1) activation / interleukin-6-mediated signaling pathway / enzyme-linked receptor protein signaling pathway / MAPK1 (ERK2) activation / Prolactin receptor signaling / positive regulation of interleukin-17 production / response to amine / signaling receptor activator activity / mesoderm development / platelet-derived growth factor receptor signaling pathway / insulin receptor substrate binding / response to tumor necrosis factor / Interleukin-3, Interleukin-5 and GM-CSF signaling / positive regulation of SMAD protein signal transduction / growth hormone receptor signaling pathway via JAK-STAT / cell surface receptor signaling pathway via JAK-STAT / type II interferon-mediated signaling pathway / Interleukin receptor SHC signaling / phosphatidylinositol 3-kinase binding / Regulation of IFNG signaling / Growth hormone receptor signaling / Signaling by CSF3 (G-CSF) / Erythropoietin activates RAS / positive regulation of T cell proliferation / tumor necrosis factor-mediated signaling pathway / positive regulation of vascular associated smooth muscle cell proliferation / extrinsic apoptotic signaling pathway / actin filament polymerization / negative regulation of cytokine production involved in inflammatory response / post-translational protein modification / cellular response to dexamethasone stimulus / SH2 domain binding / lipopolysaccharide-mediated signaling pathway / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / erythrocyte differentiation / positive regulation of interleukin-1 beta production / positive regulation of apoptotic signaling pathway / endosome lumen / positive regulation of receptor signaling pathway via JAK-STAT
Similarity search - Function
Tyrosine-protein kinase, non-receptor Jak2 / Janus kinase 2, pseudokinase domain / Janus kinase 2, catalytic domain / Tyrosine-protein kinase JAK2, SH2 domain / JAK2, FERM domain C-lobe / Tyrosine-protein kinase, non-receptor Jak/Tyk2 / JAK, FERM F2 lobe domain / FERM F1 lobe ubiquitin-like domain / JAK1-3/TYK2, pleckstrin homology-like domain / : ...Tyrosine-protein kinase, non-receptor Jak2 / Janus kinase 2, pseudokinase domain / Janus kinase 2, catalytic domain / Tyrosine-protein kinase JAK2, SH2 domain / JAK2, FERM domain C-lobe / Tyrosine-protein kinase, non-receptor Jak/Tyk2 / JAK, FERM F2 lobe domain / FERM F1 lobe ubiquitin-like domain / JAK1-3/TYK2, pleckstrin homology-like domain / : / SH2 domain / Jak1 pleckstrin homology-like domain / FERM F2 acyl-CoA binding protein-like domain / FERM F1 ubiquitin-like domain / FERM central domain / FERM superfamily, second domain / FERM domain / FERM domain profile. / Band 4.1 domain / Band 4.1 homologues / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / SH2 domain superfamily / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / PH-like domain superfamily / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
~{N}-(1~{H}-indazol-4-yl)methanesulfonamide / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.98 Å
AuthorsSoerensen, M.D. / Dack, K.N. / Greve, D.R. / Ritzen, A.
CitationJournal: Acs Med.Chem.Lett. / Year: 2016
Title: Fragment-Based Discovery of 6-Arylindazole JAK Inhibitors.
Authors: Ritzen, A. / Srensen, M.D. / Dack, K.N. / Greve, D.R. / Jerre, A. / Carnerup, M.A. / Rytved, K.A. / Bagger-Bahnsen, J.
History
DepositionApr 6, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 27, 2016Provider: repository / Type: Initial release
Revision 1.1Jun 29, 2016Group: Database references
Revision 1.2Apr 3, 2019Group: Data collection / Source and taxonomy / Category: entity_src_gen / Item: _entity_src_gen.pdbx_host_org_cell_line
Revision 1.3Oct 23, 2019Group: Data collection / Category: reflns / reflns_shell / Item: _reflns.pdbx_CC_half / _reflns_shell.pdbx_CC_half
Revision 1.4May 8, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,7422
Polymers34,5311
Non-polymers2111
Water81145
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area14870 Å2
MethodPISA
Unit cell
Length a, b, c (Å)108.140, 69.700, 50.650
Angle α, β, γ (deg.)90.00, 98.28, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Tyrosine-protein kinase JAK2 / Janus kinase 2 / JAK-2


Mass: 34530.527 Da / Num. of mol.: 1 / Mutation: Y1007F, Y1008F
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: JAK2 / Cell line (production host): Sf21 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: O60674, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-6DP / ~{N}-(1~{H}-indazol-4-yl)methanesulfonamide


Mass: 211.241 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H9N3O2S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 45 / Source method: isolated from a natural source / Formula: H2O

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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: 3.16 Å3/Da / Density % sol: 60 % / Description: plate
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / Details: 2.1M Na Malonate pH 6.0/6.5, 0.1M glycine pH 8.2 / PH range: 6-6.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I02 / Wavelength: 0.97949 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Sep 23, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97949 Å / Relative weight: 1
ReflectionResolution: 1.98→25.15 Å / Num. obs: 25595 / % possible obs: 98.4 % / Redundancy: 3.2 % / Rmerge(I) obs: 0.107 / Net I/σ(I): 8
Reflection shellResolution: 1.98→2.03 Å / Redundancy: 3.2 % / Rmerge(I) obs: 0.678 / Mean I/σ(I) obs: 3.2 / CC1/2: 0.5 / % possible all: 97.2

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Processing

Software
NameVersionClassification
REFMAC5.8.0135refinement
xia2data reduction
Aimlessdata scaling
REFMAC5.8.0135phasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.98→25.15 Å / Cor.coef. Fo:Fc: 0.929 / Cor.coef. Fo:Fc free: 0.898 / SU B: 12.006 / SU ML: 0.152 / Cross valid method: THROUGHOUT / ESU R: 0.195 / ESU R Free: 0.178 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.27657 1303 5.1 %RANDOM
Rwork0.2333 ---
obs0.23547 24289 98.27 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 40.346 Å2
Baniso -1Baniso -2Baniso -3
1-0.56 Å2-0 Å21.68 Å2
2---1.18 Å2-0 Å2
3---0.12 Å2
Refinement stepCycle: 1 / Resolution: 1.98→25.15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2389 0 14 45 2448
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0192464
X-RAY DIFFRACTIONr_bond_other_d0.0020.022345
X-RAY DIFFRACTIONr_angle_refined_deg1.3021.9683322
X-RAY DIFFRACTIONr_angle_other_deg0.93835397
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7965291
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.60924.016127
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.09815456
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.7451519
X-RAY DIFFRACTIONr_chiral_restr0.0770.2348
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0212836
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02591
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.9912.0471165
X-RAY DIFFRACTIONr_mcbond_other0.9852.0451163
X-RAY DIFFRACTIONr_mcangle_it1.8383.0641456
X-RAY DIFFRACTIONr_mcangle_other1.8373.0631456
X-RAY DIFFRACTIONr_scbond_it0.6232.1291299
X-RAY DIFFRACTIONr_scbond_other0.6222.1291299
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other1.2123.1611867
X-RAY DIFFRACTIONr_long_range_B_refined3.23715.5362672
X-RAY DIFFRACTIONr_long_range_B_other3.21415.4892658
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.98→2.031 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.447 69 -
Rwork0.364 1792 -
obs--97.13 %
Refinement TLS params.Method: refined / Origin x: 19.972 Å / Origin y: -13.22 Å / Origin z: -12.439 Å
111213212223313233
T0.0354 Å20.0062 Å20.0437 Å2-0.0365 Å20.0138 Å2--0.0815 Å2
L0.671 °20.2034 °20.1945 °2-1.1738 °20.3729 °2--1.1665 °2
S-0.051 Å °0.0624 Å °0.0137 Å °-0.1043 Å °0.0446 Å °-0.0192 Å °-0.0151 Å °0.0286 Å °0.0065 Å °

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