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- PDB-8c0a: Crystal structure of JAK2 JH2-R683S -

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Basic information

Entry
Database: PDB / ID: 8c0a
TitleCrystal structure of JAK2 JH2-R683S
ComponentsTyrosine-protein kinase JAK2
KeywordsTRANSFERASE / Janus kinase / pseudokinase / JAK2 / JH2
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 natural killer cell proliferation / positive regulation of interleukin-17 production / 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 / positive regulation of interleukin-1 beta production / endosome lumen / 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
Chem-T7I / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 Å
AuthorsHaikarainen, T. / Silvennoinen, O.
Funding support Finland, 1items
OrganizationGrant numberCountry
Academy of Finland Finland
CitationJournal: Sci Adv / Year: 2024
Title: Molecular basis of JAK2 activation in erythropoietin receptor and pathogenic JAK2 signaling.
Authors: Abraham, B.G. / Haikarainen, T. / Vuorio, J. / Girych, M. / Virtanen, A.T. / Kurttila, A. / Karathanasis, C. / Heilemann, M. / Sharma, V. / Vattulainen, I. / Silvennoinen, O.
History
DepositionDec 16, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 27, 2023Provider: repository / Type: Initial release
Revision 1.1Mar 20, 2024Group: 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.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Oct 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
B: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)66,9976
Polymers66,1022
Non-polymers8954
Water7,692427
1
A: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,4983
Polymers33,0511
Non-polymers4472
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,4983
Polymers33,0511
Non-polymers4472
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)45.980, 56.695, 60.619
Angle α, β, γ (deg.)89.900, 79.580, 71.310
Int Tables number1
Space group name H-MP1
Space group name HallP1
Symmetry operation#1: x,y,z

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Components

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


Mass: 33050.848 Da / Num. of mol.: 2 / Mutation: W659A, W777A, F794H, R683S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: JAK2 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: O60674, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-T7I / 3,5-diphenyl-2-(trifluoromethyl)-1~{H}-pyrazolo[1,5-a]pyrimidin-7-one


Mass: 355.313 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H12F3N3O / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 427 / 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: 2.22 Å3/Da / Density % sol: 44.67 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 8 / Details: 0.1 M Tris pH 8.0, 21% PEG4000, 0.1M Na-acetate

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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 24, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 1.7→59.511 Å / Num. obs: 119363 / % possible obs: 95 % / Redundancy: 1.82 % / Biso Wilson estimate: 23.74 Å2 / CC1/2: 0.997 / Net I/σ(I): 7.44
Reflection shellResolution: 1.7→1.8 Å / Redundancy: 1.83 % / Mean I/σ(I) obs: 1.07 / Num. unique obs: 19114 / CC1/2: 0.5 / % possible all: 94.2

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Processing

Software
NameVersionClassification
GDAdata collection
PHENIX1.20.1_4487refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4FVR

4fvr


Resolution: 1.7→53.61 Å / SU ML: 0.2679 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 29.256
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2375 5968 5 %
Rwork0.194 113336 -
obs0.1962 119304 95 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 30.97 Å2
Refinement stepCycle: LAST / Resolution: 1.7→53.61 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4325 0 64 427 4816
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.024536
X-RAY DIFFRACTIONf_angle_d1.52316162
X-RAY DIFFRACTIONf_chiral_restr0.0912679
X-RAY DIFFRACTIONf_plane_restr0.0141794
X-RAY DIFFRACTIONf_dihedral_angle_d14.42251674
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.7-1.720.40911970.38723726X-RAY DIFFRACTION92.74
1.72-1.740.421940.37943669X-RAY DIFFRACTION94.17
1.74-1.760.35122040.37593834X-RAY DIFFRACTION95.15
1.76-1.780.39941980.353772X-RAY DIFFRACTION94.7
1.78-1.810.41021920.3413679X-RAY DIFFRACTION94.74
1.81-1.830.34662080.31853934X-RAY DIFFRACTION95.09
1.83-1.860.3431960.30513663X-RAY DIFFRACTION94.86
1.86-1.880.30251990.27693761X-RAY DIFFRACTION94.15
1.88-1.910.30352000.26653772X-RAY DIFFRACTION95.3
1.91-1.940.2882010.24443791X-RAY DIFFRACTION94.78
1.94-1.980.26751950.24423740X-RAY DIFFRACTION94.59
1.98-2.010.2782010.22883795X-RAY DIFFRACTION95.28
2.01-2.050.2661950.22523708X-RAY DIFFRACTION94.69
2.05-2.090.24362090.20643904X-RAY DIFFRACTION95.03
2.09-2.140.24391940.19483688X-RAY DIFFRACTION95.33
2.14-2.190.24762040.18643857X-RAY DIFFRACTION95.37
2.19-2.240.23151990.1843782X-RAY DIFFRACTION95.15
2.24-2.310.22871950.17393784X-RAY DIFFRACTION95.97
2.31-2.370.23232030.18013813X-RAY DIFFRACTION95.94
2.37-2.450.23631980.17393809X-RAY DIFFRACTION95.86
2.45-2.540.23752000.1793785X-RAY DIFFRACTION95.24
2.54-2.640.22951970.183815X-RAY DIFFRACTION95.12
2.64-2.760.25211990.18573790X-RAY DIFFRACTION94.89
2.76-2.90.25071990.19363756X-RAY DIFFRACTION95.16
2.9-3.090.25342000.18653794X-RAY DIFFRACTION95.96
3.09-3.320.21711980.17743824X-RAY DIFFRACTION95.49
3.32-3.660.2331960.16963756X-RAY DIFFRACTION95.18
3.66-4.190.18952020.15033773X-RAY DIFFRACTION93.88
4.19-5.280.15922000.14723747X-RAY DIFFRACTION95.11
5.28-53.610.22091950.18843815X-RAY DIFFRACTION95.34

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