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- PDB-2b7a: The structural basis of Janus Kinase 2 inhibition by a potent and... -

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Basic information

Entry
Database: PDB / ID: 2b7a
TitleThe structural basis of Janus Kinase 2 inhibition by a potent and specific pan-Janus kinase inhibitor
ComponentsTyrosine-protein kinase JAK2
KeywordsTRANSFERASE / 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 / granulocyte macrophage colony-stimulating factor receptor complex ...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 / granulocyte macrophage colony-stimulating factor receptor complex / granulocyte-macrophage colony-stimulating factor signaling pathway / Signaling by Erythropoietin / 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 / activation of Janus kinase activity / interleukin-12 receptor complex / interleukin-23 receptor complex / positive regulation of platelet aggregation / tyrosine phosphorylation of STAT protein / positive regulation of platelet activation / positive regulation of MHC class II biosynthetic process / Interleukin-23 signaling / positive regulation of T-helper 17 type immune response / type 1 angiotensin receptor binding / positive regulation of NK T cell proliferation / acetylcholine receptor binding / interleukin-12-mediated signaling pathway / interleukin-3-mediated signaling pathway / regulation of nitric oxide biosynthetic process / cellular response to interleukin-3 / Signaling by Leptin / positive regulation of signaling receptor activity / Interleukin-12 signaling / 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 / peptide hormone receptor binding / growth hormone receptor signaling pathway / intrinsic apoptotic signaling pathway in response to oxidative stress / extrinsic component of plasma membrane / IFNG signaling activates MAPKs / 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 / positive regulation of apoptotic signaling pathway / extrinsic 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 / actin filament polymerization / extrinsic component of cytoplasmic side of plasma membrane / 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
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 / Jak1 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 / 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 / SH2 domain / 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. / PH-like domain superfamily / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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
Chem-IZA / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsLucet, I.S. / Fantino, E. / Styles, M. / Bamert, R. / Patel, O. / Broughton, S.E. / Walter, M. / Burns, C.J. / Treutlein, H. / Wilks, A.F. / Rossjohn, J.
CitationJournal: Blood / Year: 2006
Title: The structural basis of Janus kinase 2 inhibition by a potent and specific pan-Janus kinase inhibitor.
Authors: Lucet, I.S. / Fantino, E. / Styles, M. / Bamert, R. / Patel, O. / Broughton, S.E. / Walter, M. / Burns, C.J. / Treutlein, H. / Wilks, A.F. / Rossjohn, J.
History
DepositionOct 4, 2005Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Jan 10, 2006Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Oct 11, 2017Group: Refinement description / Category: software
Revision 1.4Nov 10, 2021Group: Database references / Derived calculations
Category: database_2 / struct_conn ...database_2 / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.5Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.6Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Tyrosine-protein kinase JAK2
B: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,8034
Polymers69,1852
Non-polymers6192
Water7,116395
1
A: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,9022
Polymers34,5921
Non-polymers3091
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,9022
Polymers34,5921
Non-polymers3091
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)111.273, 111.273, 70.577
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number76
Space group name H-MP41

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Components

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


Mass: 34592.383 Da / Num. of mol.: 2 / Fragment: catalytic domain / Mutation: N1129Q
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: JAK2 / Plasmid: pFastBac / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: O60674, EC: 2.7.1.112
#2: Chemical ChemComp-IZA / 2-TERT-BUTYL-9-FLUORO-3,6-DIHYDRO-7H-BENZ[H]-IMIDAZ[4,5-F]ISOQUINOLINE-7-ONE / 2-(1,1-DIMETHYLETHYL)9-FLUORO-3,6-DIHYDRO-7H-BENZ[H]-IMIDAZ[4,5-F]ISOQUINOLIN-7-ONE


Mass: 309.338 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H16FN3O
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 395 / 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: 61.03 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 28% PEG 8000, 0.2M ammonium acetate, 0.1M citrate, pH 6.0, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU300 / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Feb 2, 2004
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2→100 Å / Num. all: 146053 / Num. obs: 53644 / % possible obs: 96.8 % / Redundancy: 2.7 % / Rmerge(I) obs: 0.065 / Net I/σ(I): 15.95
Reflection shellResolution: 2→2.07 Å / Redundancy: 2.4 % / Rmerge(I) obs: 0.55 / Mean I/σ(I) obs: 2.12 / % possible all: 97.1

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Processing

Software
NameVersionClassification
REFMAC5.2.0005refinement
SCALEPACKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1M14

1m14


Resolution: 2→100 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.933 / SU B: 8.659 / SU ML: 0.123 / Cross valid method: THROUGHOUT / σ(I): 2 / ESU R: 0.171 / ESU R Free: 0.16 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24927 2861 5.1 %RANDOM
Rwork0.20881 ---
obs0.2108 53644 96.86 %-
all-146053 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 39.233 Å2
Baniso -1Baniso -2Baniso -3
1-0.98 Å20 Å20 Å2
2--0.98 Å20 Å2
3----1.96 Å2
Refinement stepCycle: LAST / Resolution: 2→100 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4762 0 46 395 5203
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0224917
X-RAY DIFFRACTIONr_angle_refined_deg1.021.9856641
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.735571
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.84424.263251
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.2415910
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.5981534
X-RAY DIFFRACTIONr_chiral_restr0.060.2690
X-RAY DIFFRACTIONr_gen_planes_refined0.0020.023730
X-RAY DIFFRACTIONr_nbd_refined0.1610.22336
X-RAY DIFFRACTIONr_nbtor_refined0.2970.23341
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.0890.2450
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1180.270
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1180.221
X-RAY DIFFRACTIONr_mcbond_it0.8532987
X-RAY DIFFRACTIONr_mcangle_it1.43454638
X-RAY DIFFRACTIONr_scbond_it1.98972401
X-RAY DIFFRACTIONr_scangle_it3.144102003
LS refinement shellResolution: 2.001→2.053 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.348 201 -
Rwork0.3 3980 -
obs--96.8 %

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