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- PDB-6wtn: Human JAK2 JH1 domain in complex with Ruxolitinib -

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Basic information

Entry
Database: PDB / ID: 6wtn
TitleHuman JAK2 JH1 domain in complex with Ruxolitinib
ComponentsTyrosine-protein kinase JAK2
KeywordsTRANSFERASE / Phosphorylation
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 / granulocyte macrophage colony-stimulating factor receptor complex ...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 / 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 / interleukin-5-mediated signaling pathway / response to interleukin-12 / Erythropoietin activates Phospholipase C gamma (PLCG) / positive regulation of leukocyte proliferation / post-embryonic hemopoiesis / erythropoietin-mediated signaling pathway / interleukin-12 receptor complex / activation of Janus kinase activity / tyrosine phosphorylation of STAT protein / interleukin-23 receptor complex / Interleukin-23 signaling / positive regulation of platelet aggregation / positive regulation of T-helper 17 type immune response / positive regulation of MHC class II biosynthetic process / interleukin-12-mediated signaling pathway / acetylcholine receptor binding / type 1 angiotensin receptor binding / positive regulation of NK T cell proliferation / positive regulation of platelet activation / cellular response to interleukin-3 / interleukin-3-mediated signaling pathway / regulation of nitric oxide biosynthetic process / Signaling by Leptin / Interleukin-12 signaling / Interleukin-27 signaling / positive regulation of signaling receptor activity / 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 / growth hormone receptor signaling pathway / axon regeneration / response to hydroperoxide / negative regulation of cardiac muscle cell apoptotic process / intrinsic apoptotic signaling pathway in response to oxidative stress / extrinsic component of plasma membrane / peptide hormone receptor binding / Interleukin-20 family signaling / IFNG signaling activates MAPKs / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / negative regulation of cell-cell adhesion / Interleukin-6 signaling / 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 / extrinsic component of cytoplasmic side of plasma membrane / mesoderm development / : / positive regulation of interleukin-17 production / 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 / type II interferon-mediated signaling pathway / growth hormone receptor signaling pathway via JAK-STAT / Interleukin receptor SHC signaling / response to tumor necrosis factor / phosphatidylinositol 3-kinase binding / Regulation of IFNG signaling / Erythropoietin activates RAS / Signaling by CSF3 (G-CSF) / Growth hormone receptor signaling / positive regulation of T cell proliferation / positive regulation of tyrosine phosphorylation of STAT protein / positive regulation of vascular associated smooth muscle cell proliferation / tumor necrosis factor-mediated signaling pathway / extrinsic apoptotic signaling pathway / post-translational protein modification / actin filament polymerization / 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
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 / SH2 domain / 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 / SH2 domain / 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 / 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 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-RXT / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.83 Å
AuthorsYu, S. / Nithianantham, S. / Fischer, M.
CitationJournal: Blood / Year: 2021
Title: Degradation of Janus kinases in CRLF2-rearranged acute lymphoblastic leukemia.
Authors: Chang, Y. / Min, J. / Jarusiewicz, J.A. / Actis, M. / Yu-Chen Bradford, S. / Mayasundari, A. / Yang, L. / Chepyala, D. / Alcock, L.J. / Roberts, K.G. / Nithianantham, S. / Maxwell, D. / ...Authors: Chang, Y. / Min, J. / Jarusiewicz, J.A. / Actis, M. / Yu-Chen Bradford, S. / Mayasundari, A. / Yang, L. / Chepyala, D. / Alcock, L.J. / Roberts, K.G. / Nithianantham, S. / Maxwell, D. / Rowland, L. / Larsen, R. / Seth, A. / Goto, H. / Imamura, T. / Akahane, K. / Hansen, B.S. / Pruett-Miller, S.M. / Paietta, E.M. / Litzow, M.R. / Qu, C. / Yang, J.J. / Fischer, M. / Rankovic, Z. / Mullighan, C.G.
History
DepositionMay 3, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 5, 2021Provider: repository / Type: Initial release
Revision 1.1Jun 30, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_id_CSD ..._citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Dec 22, 2021Group: Database references / Category: citation / citation_author / database_2
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID / _citation_author.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.4Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2
Revision 1.5Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)36,9055
Polymers36,4121
Non-polymers4934
Water1,67593
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)78.850, 78.850, 84.827
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number152
Space group name H-MP3121

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Components

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


Mass: 36412.297 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: JAK2 / Plasmid: pFastBac / Cell (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: O60674, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-RXT / (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile / Ruxolitinib


Mass: 306.365 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H18N6 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication, inhibitor*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 93 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.09 Å3/Da / Density % sol: 41.16 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 5 / Details: 1.6-2.4 M sodium malonate, pH 5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Nov 8, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.83→36.04 Å / Num. obs: 27349 / % possible obs: 99.9 % / Redundancy: 6.6 % / CC1/2: 0.998 / Rmerge(I) obs: 0.076 / Rpim(I) all: 0.032 / Rrim(I) all: 0.083 / Net I/σ(I): 10.8 / Num. measured all: 179497 / Scaling rejects: 173
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.83-1.886.40.8351266319920.7180.3530.9082.199.9
8.18-36.045.80.03721233630.9990.0160.04123.799.3

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Processing

Software
NameVersionClassification
Aimless0.7.3data scaling
PHENIX1.17refinement
PDB_EXTRACT3.25data extraction
xia2data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5USY

5usy


Resolution: 1.83→36.03 Å / SU ML: 0.19 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 20.41 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2084 1376 5.04 %
Rwork0.1872 25937 -
obs0.1883 27313 99.73 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 149.4 Å2 / Biso mean: 41.6108 Å2 / Biso min: 15.23 Å2
Refinement stepCycle: final / Resolution: 1.83→36.03 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2285 0 35 93 2413
Biso mean--40.19 46.68 -
Num. residues----287
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 10

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.83-1.890.27741360.23462518265499
1.89-1.970.23421340.210625782712100
1.97-2.060.22851340.186825542688100
2.06-2.170.22791350.174325622697100
2.17-2.30.20311370.176725742711100
2.3-2.480.21141400.171725712711100
2.48-2.730.20091350.176926052740100
2.73-3.130.21711380.183426072745100
3.13-3.940.18511400.176126302770100
3.94-36.030.19961470.187627382885100
Refinement TLS params.Method: refined / Origin x: 30.3808 Å / Origin y: 8.3924 Å / Origin z: 8.6644 Å
111213212223313233
T0.2019 Å2-0.0471 Å2-0.025 Å2-0.1807 Å2-0.0149 Å2--0.1799 Å2
L1.5152 °20.2895 °20.9086 °2-1.4194 °20.2721 °2--1.3623 °2
S0.1478 Å °-0.3446 Å °-0.1009 Å °0.0106 Å °-0.1597 Å °0.125 Å °0.1227 Å °-0.195 Å °-0.0138 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA843 - 1135
2X-RAY DIFFRACTION1allC102 - 105
3X-RAY DIFFRACTION1allD1 - 95
4X-RAY DIFFRACTION1allB1

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