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- PDB-5wim: JAK2 Pseudokinase in complex with AT9283 -

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Basic information

Entry
Database: PDB / ID: 5wim
TitleJAK2 Pseudokinase in complex with AT9283
ComponentsTyrosine-protein kinase JAK2
KeywordsTRANSFERASE / JAK2 / Pseudokinase / AT9283
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 / response to interleukin-12 / interleukin-5-mediated signaling pathway / 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 / interleukin-3-mediated signaling pathway / cellular response to interleukin-3 / regulation of nitric oxide biosynthetic process / Signaling by Leptin / Interleukin-12 signaling / Interleukin-27 signaling / IL-6-type cytokine receptor ligand interactions / Interleukin-35 Signalling / positive regulation of signaling receptor activity / 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 / Interleukin-6 signaling / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / negative regulation of cell-cell adhesion / 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 nitric-oxide synthase biosynthetic process / 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 / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / erythrocyte differentiation / 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 / 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-35R / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.55 Å
AuthorsLi, Q. / Eck, M.J. / Li, K. / Park, E.
CitationJournal: ACS Chem. Biol. / Year: 2019
Title: Discovery and Structural Characterization of ATP-Site Ligands for the Wild-Type and V617F Mutant JAK2 Pseudokinase Domain.
Authors: McNally, R. / Li, Q. / Li, K. / Dekker, C. / Vangrevelinghe, E. / Jones, M. / Chene, P. / Machauer, R. / Radimerski, T. / Eck, M.J.
History
DepositionJul 19, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 1, 2018Provider: repository / Type: Initial release
Revision 1.1Mar 20, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _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 1.2May 1, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.3Mar 13, 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)32,0632
Polymers31,6811
Non-polymers3811
Water39622
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)57.791, 60.687, 89.600
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 31681.367 Da / Num. of mol.: 1 / Fragment: UNP residues 536-812 / Mutation: W659A, W777A, F794H
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-35R / 1-cyclopropyl-3-{3-[5-(morpholin-4-ylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}urea


Mass: 381.432 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H23N7O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 22 / 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: 2.46 Å3/Da / Density % sol: 50.02 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 8
Details: 200 mM Sodium Acetate, 100 mM Tris-HCl, 18%-30%(w/v) polyethylene glycol 4000.
PH range: 7.5-8.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.987 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Feb 19, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 2.55→50 Å / Num. obs: 10739 / % possible obs: 99.75 % / Redundancy: 5.8 % / Biso Wilson estimate: 36.6 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.102 / Rpim(I) all: 0.068 / Rsym value: 0.123 / Net I/σ(I): 14.3
Reflection shellResolution: 2.55→2.641 Å / Redundancy: 5.9 % / Rmerge(I) obs: 0.729 / Mean I/σ(I) obs: 3 / Num. unique obs: 1054 / CC1/2: 0.939 / Rpim(I) all: 0.485 / Rsym value: 0.878 / % possible all: 99.34

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Processing

Software
NameVersionClassification
PHENIX(1.11.1_2575: ???)refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementResolution: 2.55→48.565 Å / SU ML: 0.27 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 29.37 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2584 507 4.73 %
Rwork0.2086 --
obs0.2109 10723 99.76 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.55→48.565 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2205 0 28 22 2255
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082286
X-RAY DIFFRACTIONf_angle_d1.0833092
X-RAY DIFFRACTIONf_dihedral_angle_d18.3771378
X-RAY DIFFRACTIONf_chiral_restr0.047338
X-RAY DIFFRACTIONf_plane_restr0.007397
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.5502-2.80680.35421150.27252502X-RAY DIFFRACTION100
2.8068-3.21280.33531250.24122520X-RAY DIFFRACTION100
3.2128-4.04750.23931340.2032529X-RAY DIFFRACTION100
4.0475-48.57420.21641330.18172665X-RAY DIFFRACTION100

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