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- PDB-8bpw: Crystal structure of JAK2 JH1 in complex with lestaurtinib -

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Entry
Database: PDB / ID: 8bpw
TitleCrystal structure of JAK2 JH1 in complex with lestaurtinib
ComponentsTyrosine-protein kinase JAK2
KeywordsTRANSFERASE / Janus kinase / inhibitor complex / JAK2 / JH1
Function / homology
Function and homology information


interleukin-35-mediated signaling pathway / nuclear receptor-mediated mineralocorticoid signaling pathway / histone H3Y41 kinase activity / symbiont-induced defense-related programmed cell death / regulation of postsynapse to nucleus signaling pathway / positive regulation of growth hormone receptor signaling pathway / positive regulation of growth factor dependent skeletal muscle satellite cell proliferation / mammary gland epithelium development / granulocyte macrophage colony-stimulating factor receptor complex / granulocyte-macrophage colony-stimulating factor signaling pathway ...interleukin-35-mediated signaling pathway / nuclear receptor-mediated mineralocorticoid signaling pathway / histone H3Y41 kinase activity / symbiont-induced defense-related programmed cell death / regulation of postsynapse to nucleus signaling pathway / positive regulation of growth hormone receptor signaling pathway / positive regulation of growth factor dependent skeletal muscle satellite cell proliferation / mammary gland epithelium development / 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 / activation of Janus kinase activity / response to interleukin-12 / Erythropoietin activates Phospholipase C gamma (PLCG) / positive regulation of leukocyte proliferation / type 1 angiotensin receptor binding / post-embryonic hemopoiesis / interleukin-12 receptor complex / erythropoietin-mediated signaling pathway / interleukin-23 receptor complex / interleukin-23-mediated signaling pathway / Interleukin-23 signaling / positive regulation of T-helper 17 type immune response / interleukin-12-mediated signaling pathway / positive regulation of MHC class II biosynthetic process / positive regulation of NK T cell proliferation / acetylcholine receptor binding / positive regulation of platelet activation / cellular response to interleukin-3 / interleukin-3-mediated signaling pathway / positive regulation of platelet aggregation / Signaling by Leptin / Interleukin-12 signaling / positive regulation of epithelial cell apoptotic process / IL-6-type cytokine receptor ligand interactions / Interleukin-27 signaling / Interleukin-35 Signalling / regulation of nitric oxide biosynthetic process / growth hormone receptor binding / positive regulation of cell-substrate adhesion / axon regeneration / response to hydroperoxide / extrinsic component of cytoplasmic side of plasma membrane / regulation of receptor signaling pathway via JAK-STAT / negative regulation of cardiac muscle cell apoptotic process / growth hormone receptor signaling pathway / intrinsic apoptotic signaling pathway in response to oxidative stress / positive regulation of tyrosine phosphorylation of STAT protein / negative regulation of cell-cell adhesion / extrinsic component of plasma membrane / Interleukin-20 family signaling / IFNG signaling activates MAPKs / Interleukin-6 signaling / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / peptide hormone receptor binding / enzyme-linked receptor protein signaling pathway / interleukin-6-mediated signaling pathway / MAPK3 (ERK1) activation / response to amine / Prolactin receptor signaling / MAPK1 (ERK2) activation / platelet-derived growth factor receptor signaling pathway / mesoderm development / positive regulation of interleukin-17 production / positive regulation of natural killer cell proliferation / response to tumor necrosis factor / signaling receptor activator activity / Interleukin-3, Interleukin-5 and GM-CSF signaling / positive regulation of SMAD protein signal transduction / insulin receptor substrate binding / growth hormone receptor signaling pathway via JAK-STAT / Interleukin receptor SHC signaling / cell surface receptor signaling pathway via JAK-STAT / cellular response to dexamethasone stimulus / type II interferon-mediated signaling pathway / Regulation of IFNG signaling / Growth hormone receptor signaling / Erythropoietin activates RAS / phosphatidylinositol 3-kinase binding / Signaling by CSF3 (G-CSF) / positive regulation of vascular associated smooth muscle cell proliferation / extrinsic apoptotic signaling pathway / actin filament polymerization / positive regulation of T cell proliferation / negative regulation of cytokine production involved in inflammatory response / SH2 domain binding / post-translational protein modification / lipopolysaccharide-mediated signaling pathway / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / endosome lumen / positive regulation of interleukin-1 beta production / positive regulation of apoptotic signaling pathway / erythrocyte differentiation / tumor necrosis factor-mediated signaling pathway / non-membrane spanning protein tyrosine kinase activity
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 / : / Jak1 pleckstrin homology-like domain / FERM F2 acyl-CoA binding protein-like domain / FERM F1 ubiquitin-like domain / SH2 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. / PH-like domain superfamily / Tyrosine-protein kinase, active site / 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
Lestaurtinib / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsMiao, Y. / Haikarainen, T.
Funding support Finland, 1items
OrganizationGrant numberCountry
Academy of Finland Finland
CitationJournal: J.Med.Chem. / Year: 2024
Title: Functional and Structural Characterization of Clinical-Stage Janus Kinase 2 Inhibitors Identifies Determinants for Drug Selectivity.
Authors: Miao, Y. / Virtanen, A. / Zmajkovic, J. / Hilpert, M. / Skoda, R.C. / Silvennoinen, O. / Haikarainen, T.
History
DepositionNov 18, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 29, 2023Provider: repository / Type: Initial release
Revision 1.1Jul 10, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Nov 20, 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
B: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,5304
Polymers74,6512
Non-polymers8792
Water9,476526
1
A: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,7652
Polymers37,3251
Non-polymers4391
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,7652
Polymers37,3251
Non-polymers4391
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)99.525, 69.512, 110.890
Angle α, β, γ (deg.)90.000, 98.700, 90.000
Int Tables number5
Space group name H-MI121
Space group name HallC2y(x,y,-x+z)
Symmetry operation#1: x,y,z
#2: -x,y,-z
#3: x+1/2,y+1/2,z+1/2
#4: -x+1/2,y+1/2,-z+1/2
Components on special symmetry positions
IDModelComponents
11B-1526-

HOH

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Components

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


Mass: 37325.336 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: JAK2 / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: O60674, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-2V9 / Lestaurtinib / (5S,6S,8R)-6-hydroxy-6-(hydroxymethyl)-5-methyl-5,6,7,8-tetrahydro-13H-5,8-epoxy-4b,8a,14-triazadibenzo[b,h]cycloocta[1,2,3,4-jkl]cyclopenta[e]-as-indacen-13-one


Mass: 439.463 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H21N3O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 526 / 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: 2.54 Å3/Da / Density % sol: 51.57 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 8.2 / Details: 2 M Na-malonate, 0.1 M Gly-Gly pH 8.2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97625 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Nov 29, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 1.8→79.43 Å / Num. obs: 69470 / % possible obs: 99.9 % / Redundancy: 6.9 % / CC1/2: 0.999 / Net I/σ(I): 14.7
Reflection shellResolution: 1.8→1.84 Å / Num. unique obs: 4105 / CC1/2: 0.762

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Processing

Software
NameVersionClassification
GDAdata collection
PHENIX1.20.1_4487refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6vn8

6vn8


Resolution: 1.8→68.26 Å / SU ML: 0.1688 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 21.14
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1966 3460 4.99 %
Rwork0.1612 65945 -
obs0.163 69405 99.83 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 29.57 Å2
Refinement stepCycle: LAST / Resolution: 1.8→68.26 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4928 0 66 526 5520
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01065172
X-RAY DIFFRACTIONf_angle_d1.22197021
X-RAY DIFFRACTIONf_chiral_restr0.0657731
X-RAY DIFFRACTIONf_plane_restr0.0134899
X-RAY DIFFRACTIONf_dihedral_angle_d14.16271955
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8-1.820.29621460.25762585X-RAY DIFFRACTION98.52
1.82-1.850.29931410.24552623X-RAY DIFFRACTION99.93
1.85-1.880.25841150.22442682X-RAY DIFFRACTION99.89
1.88-1.910.25841260.19852584X-RAY DIFFRACTION100
1.91-1.940.2351270.19662644X-RAY DIFFRACTION99.93
1.94-1.970.22541570.19922611X-RAY DIFFRACTION99.78
1.97-2.010.26541280.18792610X-RAY DIFFRACTION99.89
2.01-2.050.21751360.1722669X-RAY DIFFRACTION100
2.05-2.090.16891270.16352646X-RAY DIFFRACTION100
2.09-2.130.19871260.1462628X-RAY DIFFRACTION99.96
2.13-2.180.191310.14882646X-RAY DIFFRACTION100
2.18-2.240.19021350.14122618X-RAY DIFFRACTION99.89
2.24-2.30.20241320.14512625X-RAY DIFFRACTION99.93
2.3-2.370.20691450.1472637X-RAY DIFFRACTION100
2.37-2.440.20541220.14652637X-RAY DIFFRACTION100
2.44-2.530.19851500.15622633X-RAY DIFFRACTION100
2.53-2.630.19281490.15062651X-RAY DIFFRACTION99.96
2.63-2.750.17751500.15072631X-RAY DIFFRACTION99.96
2.75-2.90.18571390.15932642X-RAY DIFFRACTION99.96
2.9-3.080.20171470.16182626X-RAY DIFFRACTION99.93
3.08-3.310.21111350.1642646X-RAY DIFFRACTION99.86
3.31-3.650.19381360.14442680X-RAY DIFFRACTION99.96
3.65-4.180.15741570.13232633X-RAY DIFFRACTION99.96
4.18-5.260.15331380.14252672X-RAY DIFFRACTION99.82
5.26-68.260.22361650.21012686X-RAY DIFFRACTION98.82

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