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- PDB-8b9e: Crystal structure of JAK2 JH2-V617F in complex with Z902-A3 -

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Basic information

Entry
Database: PDB / ID: 8b9e
TitleCrystal structure of JAK2 JH2-V617F in complex with Z902-A3
ComponentsTyrosine-protein kinase JAK2
KeywordsTRANSFERASE / Janus kinase / pseudokinase / inhibitor complex / JAK2 / JH2
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-12 receptor binding / Erythropoietin activates STAT5 / interleukin-5-mediated signaling pathway / Erythropoietin activates Phospholipase C gamma (PLCG) / response to interleukin-12 / 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-mediated signaling pathway / Interleukin-23 signaling / positive regulation of T-helper 17 type immune response / positive regulation of MHC class II biosynthetic process / positive regulation of platelet aggregation / 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 / positive regulation of signaling receptor activity / Interleukin-27 signaling / 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 / negative regulation of DNA binding / response to amine / : / extrinsic component of cytoplasmic side of plasma membrane / positive regulation of interleukin-17 production / mesoderm development / 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 / Interleukin-3, Interleukin-5 and GM-CSF signaling / insulin receptor substrate binding / growth hormone receptor signaling pathway via JAK-STAT / Interleukin receptor SHC signaling / response to tumor necrosis factor / type II interferon-mediated signaling pathway / phosphatidylinositol 3-kinase binding / Regulation of IFNG signaling / Erythropoietin activates RAS / Growth hormone receptor signaling / Signaling by CSF3 (G-CSF) / positive regulation of tyrosine phosphorylation of STAT protein / positive regulation of T cell proliferation / tumor necrosis factor-mediated signaling pathway / extrinsic apoptotic signaling pathway / positive regulation of vascular associated smooth muscle cell proliferation / 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 / 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-Q7F / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.5 Å
AuthorsHaikarainen, T. / Silvennoinen, O.
Funding support Finland, 1items
OrganizationGrant numberCountry
Academy of Finland Finland
CitationJournal: Pharmaceuticals / Year: 2023
Title: Identification of Novel Small Molecule Ligands for JAK2 Pseudokinase Domain.
Authors: Virtanen, A.T. / Haikarainen, T. / Sampathkumar, P. / Palmroth, M. / Liukkonen, S. / Liu, J. / Nekhotiaeva, N. / Hubbard, S.R. / Silvennoinen, O.
History
DepositionOct 5, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 1, 2023Provider: repository / Type: Initial release
Revision 1.1Feb 7, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,8094
Polymers33,2841
Non-polymers5253
Water6,251347
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area310 Å2
ΔGint-1 kcal/mol
Surface area13490 Å2
Unit cell
Length a, b, c (Å)53.466, 56.555, 114.932
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

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


Mass: 33284.133 Da / Num. of mol.: 1 / Mutation: W777A, F794H, V617F
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-Q7F / 6-[[methyl-[(3-methylthiophen-2-yl)methyl]amino]methyl]-~{N}4-phenyl-1,3,5-triazine-2,4-diamine


Mass: 340.446 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H20N6S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 347 / 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: 2.61 Å3/Da / Density % sol: 52.88 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 8 / Details: 0.1M Tris pH 8, 20% PEG4000, 0.2M 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: Jul 3, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 1.5→57.466 Å / Num. obs: 98889 / % possible obs: 91.6 % / Redundancy: 6.1 % / Biso Wilson estimate: 22.61 Å2 / CC1/2: 0.999 / Net I/σ(I): 13.68
Reflection shellResolution: 1.5→1.59 Å / Redundancy: 3.4 % / Mean I/σ(I) obs: 0.77 / Num. unique obs: 10775 / CC1/2: 0.915 / % possible all: 61.5

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Processing

Software
NameVersionClassification
GDAdata collection
PHENIX1.19.2_4158refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4fvr

4fvr


Resolution: 1.5→40.31 Å / SU ML: 0.1993 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 23.6009
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1938 4955 5.01 %
Rwork0.1689 93913 -
obs0.1702 98868 91.56 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 31.55 Å2
Refinement stepCycle: LAST / Resolution: 1.5→40.31 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2194 0 36 347 2577
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01662357
X-RAY DIFFRACTIONf_angle_d1.26783209
X-RAY DIFFRACTIONf_chiral_restr0.1063350
X-RAY DIFFRACTIONf_plane_restr0.0121417
X-RAY DIFFRACTIONf_dihedral_angle_d16.7566893
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.5-1.520.391990.3711786X-RAY DIFFRACTION51.99
1.52-1.530.38091040.37421923X-RAY DIFFRACTION56.09
1.53-1.550.39951100.3362104X-RAY DIFFRACTION62.47
1.55-1.570.33851230.31652298X-RAY DIFFRACTION66.02
1.57-1.590.36021270.30662471X-RAY DIFFRACTION73.37
1.59-1.620.29881430.29152683X-RAY DIFFRACTION76.5
1.62-1.640.29641480.27462776X-RAY DIFFRACTION83.42
1.64-1.660.27431620.273097X-RAY DIFFRACTION88.9
1.66-1.690.31291650.27453184X-RAY DIFFRACTION94.26
1.69-1.720.30221800.2623336X-RAY DIFFRACTION97.64
1.72-1.750.26361740.23013326X-RAY DIFFRACTION98.26
1.75-1.780.21411840.20963462X-RAY DIFFRACTION99.54
1.78-1.810.24951790.19613398X-RAY DIFFRACTION100
1.81-1.850.22911780.18683429X-RAY DIFFRACTION100
1.85-1.890.25521790.18723418X-RAY DIFFRACTION99.86
1.89-1.930.22191810.18223374X-RAY DIFFRACTION99.94
1.93-1.980.19731800.18273462X-RAY DIFFRACTION100
1.98-2.040.21671770.17923387X-RAY DIFFRACTION100
2.04-2.090.18391780.17063434X-RAY DIFFRACTION99.97
2.1-2.160.21041760.15683431X-RAY DIFFRACTION100
2.16-2.240.18031770.15043408X-RAY DIFFRACTION99.92
2.24-2.330.16871820.15843429X-RAY DIFFRACTION99.97
2.33-2.440.17931830.15943413X-RAY DIFFRACTION100
2.44-2.560.18741760.15423397X-RAY DIFFRACTION100
2.56-2.720.21221840.15883410X-RAY DIFFRACTION99.94
2.72-2.930.20321820.1623423X-RAY DIFFRACTION99.89
2.93-3.230.17591770.15723413X-RAY DIFFRACTION99.97
3.23-3.70.1961840.14863401X-RAY DIFFRACTION99.92
3.7-4.660.12961840.13133421X-RAY DIFFRACTION100
4.66-40.310.16271790.16333419X-RAY DIFFRACTION99.78

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