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- PDB-8ba3: Crystal structure of JAK2 JH2 in complex with Bemcentinib -

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Basic information

Entry
Database: PDB / ID: 8ba3
TitleCrystal structure of JAK2 JH2 in complex with Bemcentinib
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 / 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 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-Q8U / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.4 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 11, 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)34,0887
Polymers33,1211
Non-polymers9676
Water4,630257
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1080 Å2
ΔGint-4 kcal/mol
Surface area14530 Å2
Unit cell
Length a, b, c (Å)78.224, 57.756, 60.633
Angle α, β, γ (deg.)90.000, 91.622, 90.000
Int Tables number5
Space group name H-MC121
Space group name HallC2y
Symmetry operation#1: x,y,z
#2: -x,y,-z
#3: x+1/2,y+1/2,z
#4: -x+1/2,y+1/2,-z

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Components

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


Mass: 33120.961 Da / Num. of mol.: 1 / Mutation: W659A, W777A, F794H
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-Q8U / 1-(3,4-diazatricyclo[9.4.0.0^{2,7}]pentadeca-1(11),2(7),3,5,12,14-hexaen-5-yl)-~{N}3-[(7~{S})-7-pyrrolidin-1-yl-6,7,8,9-tetrahydro-5~{H}-benzo[7]annulen-3-yl]-1,2,4-triazole-3,5-diamine / Bemcentinib


Mass: 506.645 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H34N8 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 257 / 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: 2.07 Å3/Da / Density % sol: 40.49 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 8 / Details: 0.1M Tris pH 8, 16% 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: Nov 24, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 1.4→60.609 Å / Num. obs: 99239 / % possible obs: 95.1 % / Redundancy: 3.3 % / Biso Wilson estimate: 18.64 Å2 / CC1/2: 0.999 / Net I/σ(I): 12.48
Reflection shellResolution: 1.4→1.49 Å / Redundancy: 2.1 % / Mean I/σ(I) obs: 1 / Num. unique obs: 12230 / CC1/2: 0.439 / % possible all: 72.6

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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: 1.4→46.46 Å / SU ML: 0.1995 / Cross valid method: FREE R-VALUE / σ(F): 1.2 / Phase error: 23.0343
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1965 4948 4.99 %
Rwork0.1737 94281 -
obs0.1749 99229 95.05 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 26.68 Å2
Refinement stepCycle: LAST / Resolution: 1.4→46.46 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2266 0 68 257 2591
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01562440
X-RAY DIFFRACTIONf_angle_d1.27263314
X-RAY DIFFRACTIONf_chiral_restr0.0923361
X-RAY DIFFRACTIONf_plane_restr0.0114423
X-RAY DIFFRACTIONf_dihedral_angle_d15.2664909
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.4-1.420.45391030.41531966X-RAY DIFFRACTION60.34
1.42-1.430.34451170.38962245X-RAY DIFFRACTION67.12
1.43-1.450.40231240.35742367X-RAY DIFFRACTION72.45
1.45-1.470.35241390.32772616X-RAY DIFFRACTION78.89
1.47-1.490.30251480.31062833X-RAY DIFFRACTION85.96
1.49-1.510.33721590.28333026X-RAY DIFFRACTION91.21
1.51-1.530.29541750.26143255X-RAY DIFFRACTION98.39
1.53-1.550.29131680.25143278X-RAY DIFFRACTION99.65
1.55-1.580.28891780.24843324X-RAY DIFFRACTION99.89
1.58-1.60.24911750.23393299X-RAY DIFFRACTION99.88
1.6-1.630.24481760.23033302X-RAY DIFFRACTION99.86
1.63-1.660.26511680.22723275X-RAY DIFFRACTION99.88
1.66-1.690.28991710.21233298X-RAY DIFFRACTION99.91
1.69-1.730.21381720.20363321X-RAY DIFFRACTION99.89
1.73-1.760.24051710.19413276X-RAY DIFFRACTION99.97
1.76-1.810.19321770.18883375X-RAY DIFFRACTION99.92
1.81-1.850.19551690.18553248X-RAY DIFFRACTION99.94
1.85-1.90.21591730.183286X-RAY DIFFRACTION99.91
1.9-1.960.18971780.17433344X-RAY DIFFRACTION99.83
1.96-2.020.21231720.16643349X-RAY DIFFRACTION99.89
2.02-2.090.20761740.17033267X-RAY DIFFRACTION99.91
2.09-2.180.19621740.15843279X-RAY DIFFRACTION99.94
2.18-2.270.18941750.15273317X-RAY DIFFRACTION100
2.27-2.390.16381730.15243308X-RAY DIFFRACTION99.89
2.39-2.540.17621760.1513325X-RAY DIFFRACTION99.97
2.54-2.740.16351730.16053284X-RAY DIFFRACTION99.57
2.74-3.020.16421720.16083304X-RAY DIFFRACTION99.91
3.02-3.450.18841720.15353302X-RAY DIFFRACTION99.88
3.45-4.350.15581720.13873330X-RAY DIFFRACTION99.94
4.35-46.460.18551740.16983282X-RAY DIFFRACTION99.68

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