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- PDB-8bx9: Crystal structure of JAK2 JH1 in complex with ilginatinib -

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Basic information

Entry
Database: PDB / ID: 8bx9
TitleCrystal structure of JAK2 JH1 in complex with ilginatinib
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 / extrinsic component of cytoplasmic side of plasma membrane / response to hydroperoxide / 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) / enzyme-linked receptor protein signaling pathway / peptide hormone receptor binding / 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 / insulin receptor substrate binding / positive regulation of SMAD protein signal transduction / 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 / phosphatidylinositol 3-kinase binding / Erythropoietin activates RAS / positive regulation of vascular associated smooth muscle cell proliferation / Signaling by CSF3 (G-CSF) / extrinsic apoptotic signaling pathway / positive regulation of T cell proliferation / actin filament polymerization / 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 / tumor necrosis factor-mediated signaling pathway / erythrocyte differentiation / 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
Ilginatinib / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.4 Å
AuthorsHaikarainen, 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
DepositionDec 8, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 20, 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 6, 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)75,4726
Polymers74,5372
Non-polymers9354
Water8,665481
1
A: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,7363
Polymers37,2681
Non-polymers4682
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,7363
Polymers37,2681
Non-polymers4682
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)99.526, 68.883, 107.956
Angle α, β, γ (deg.)90.000, 99.130, 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

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Components

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


Mass: 37268.285 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: PTR is phosphorylated tyrosine residue. / 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-S59 / Ilginatinib / ~{N}6-[(1~{S})-1-(4-fluorophenyl)ethyl]-4-(1-methylpyrazol-4-yl)-~{N}2-pyrazin-2-yl-pyridine-2,6-diamine


Mass: 389.429 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H20FN7 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 481 / 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: 2.45 Å3/Da / Density % sol: 49.81 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 8.2 / Details: 0.1 M Gly-Gly pH 8.2, 1.6 M Na-malonate

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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: 1.4→78.74 Å / Num. obs: 141301 / % possible obs: 99.7 % / Redundancy: 6.9 % / Biso Wilson estimate: 14.37 Å2 / CC1/2: 1 / Net I/σ(I): 9.8
Reflection shellResolution: 1.4→1.42 Å / Redundancy: 6.9 % / Mean I/σ(I) obs: 1.3 / Num. unique obs: 6815 / CC1/2: 0.809 / % possible all: 97.4

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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: 1.4→67.14 Å / SU ML: 0.1493 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 37.6472
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2228 7069 5.01 %
Rwork0.1913 133929 -
obs0.1929 140998 99.5 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 22.56 Å2
Refinement stepCycle: LAST / Resolution: 1.4→67.14 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4908 0 66 481 5455
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01175214
X-RAY DIFFRACTIONf_angle_d1.08597076
X-RAY DIFFRACTIONf_chiral_restr0.0827747
X-RAY DIFFRACTIONf_plane_restr0.0138916
X-RAY DIFFRACTIONf_dihedral_angle_d13.46522016
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.4-1.420.35342220.31894312X-RAY DIFFRACTION96.43
1.42-1.430.32452320.294427X-RAY DIFFRACTION99.25
1.43-1.450.31022400.26974407X-RAY DIFFRACTION99.4
1.45-1.470.32172240.25514447X-RAY DIFFRACTION99.17
1.47-1.490.30842350.25164487X-RAY DIFFRACTION99.75
1.49-1.510.2852600.24154380X-RAY DIFFRACTION99.34
1.51-1.530.27122360.23784467X-RAY DIFFRACTION99.56
1.53-1.550.27612110.22834444X-RAY DIFFRACTION99.66
1.55-1.580.28832530.22624470X-RAY DIFFRACTION99.58
1.58-1.60.24812050.22274484X-RAY DIFFRACTION99.55
1.6-1.630.27752290.21994451X-RAY DIFFRACTION99.77
1.63-1.660.24852480.20844445X-RAY DIFFRACTION99.55
1.66-1.690.22582440.20694461X-RAY DIFFRACTION99.75
1.69-1.730.22982270.19944473X-RAY DIFFRACTION99.81
1.73-1.760.25482430.194458X-RAY DIFFRACTION100
1.76-1.80.22342460.19484489X-RAY DIFFRACTION99.94
1.8-1.850.24972330.18884445X-RAY DIFFRACTION99.91
1.85-1.90.21612250.18884491X-RAY DIFFRACTION99.81
1.9-1.960.21432370.17274472X-RAY DIFFRACTION99.6
1.96-2.020.1992560.16344424X-RAY DIFFRACTION99.74
2.02-2.090.17082510.1614499X-RAY DIFFRACTION99.92
2.09-2.170.20682450.15194475X-RAY DIFFRACTION99.98
2.17-2.270.17932260.15114475X-RAY DIFFRACTION99.85
2.27-2.390.18282280.14964505X-RAY DIFFRACTION99.81
2.39-2.540.1852400.16014494X-RAY DIFFRACTION99.85
2.54-2.740.21272100.16834517X-RAY DIFFRACTION99.83
2.74-3.020.22172280.18564529X-RAY DIFFRACTION99.85
3.02-3.450.252580.18974509X-RAY DIFFRACTION99.94
3.45-4.350.17862300.18414512X-RAY DIFFRACTION99.48
4.35-67.140.23152470.21954480X-RAY DIFFRACTION97.04

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