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- PDB-6drw: JAK2 JH1 in complex with JNJ-7706621 (Crystal Form 2) -

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Basic information

Entry
Database: PDB / ID: 6drw
TitleJAK2 JH1 in complex with JNJ-7706621 (Crystal Form 2)
ComponentsTyrosine-protein kinase JAK2
KeywordsTRANSFERASE/TRANSFERASE Inhibitor / Kinase / TRANSFERASE / TRANSFERASE-TRANSFERASE Inhibitor complex
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 / interleukin-12 receptor complex / post-embryonic hemopoiesis / 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 / positive regulation of platelet activation / acetylcholine receptor binding / interleukin-3-mediated signaling pathway / positive regulation of platelet aggregation / cellular response to interleukin-3 / Interleukin-12 signaling / Signaling by Leptin / IL-6-type cytokine receptor ligand interactions / Interleukin-27 signaling / positive regulation of epithelial cell apoptotic process / Interleukin-35 Signalling / growth hormone receptor binding / regulation of nitric oxide biosynthetic process / 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 / IFNG signaling activates MAPKs / Interleukin-20 family signaling / Interleukin-6 signaling / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / enzyme-linked receptor protein signaling pathway / interleukin-6-mediated signaling pathway / peptide hormone receptor binding / response to amine / MAPK3 (ERK1) activation / Prolactin receptor signaling / MAPK1 (ERK2) activation / platelet-derived growth factor receptor signaling pathway / mesoderm development / positive regulation of interleukin-17 production / response to tumor necrosis factor / positive regulation of natural killer cell proliferation / signaling receptor activator activity / insulin receptor substrate binding / positive regulation of SMAD protein signal transduction / Interleukin-3, Interleukin-5 and GM-CSF signaling / 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 / Growth hormone receptor signaling / Regulation of IFNG 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 / post-translational protein modification / SH2 domain binding / lipopolysaccharide-mediated signaling pathway / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / endosome lumen / tumor necrosis factor-mediated signaling pathway / positive regulation of interleukin-1 beta production / erythrocyte differentiation / positive regulation of apoptotic 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-SKE / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.303 Å
AuthorsPuleo, D.E. / Schlessinger, J.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM007324 United States
Gilead SciencesYG-003-13 United States
CitationJournal: To Be Published
Title: JAK2 JH2 Binders
Authors: Puleo, D.E. / Schlessinger, J.
History
DepositionJun 13, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 18, 2018Provider: repository / Type: Initial release
Revision 1.1Jan 1, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2
Revision 1.4Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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)37,7932
Polymers37,3981
Non-polymers3941
Water2,180121
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)107.867, 69.042, 50.050
Angle α, β, γ (deg.)90.00, 99.07, 90.00
Int Tables number5
Space group name H-MC121

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Components

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


Mass: 37398.402 Da / Num. of mol.: 1
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-SKE / 4-({5-amino-1-[(2,6-difluorophenyl)carbonyl]-1H-1,2,4-triazol-3-yl}amino)benzenesulfonamide


Mass: 394.356 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H12F2N6O3S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 121 / Source method: isolated from a natural source / Formula: H2O
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: 2.46 Å3/Da / Density % sol: 50.01 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 8
Details: 0.1M Glycyl-glycine pH 8.0 2.5 M Sodium Malonate pH 6.0
PH range: 7.5-8.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.54 Å
DetectorType: DECTRIS PILATUS 200K / Detector: PIXEL / Date: Feb 19, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.3→36.104 Å / Num. obs: 15437 / % possible obs: 95.9 % / Redundancy: 2.9 % / Rsym value: 0.094 / Net I/σ(I): 8.1
Reflection shellResolution: 2.3→2.38 Å / Redundancy: 2.6 % / Mean I/σ(I) obs: 1.96 / Num. unique obs: 1460 / Rrim(I) all: 0.31 / % possible all: 91.4

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Processing

Software
NameVersionClassification
PHENIX(1.13_2998: ???)refinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2B7A

2b7a


Resolution: 2.303→36.104 Å / SU ML: 0.31 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 27.66
RfactorNum. reflection% reflection
Rfree0.2552 704 4.59 %
Rwork0.2143 --
obs0.2162 15323 94.75 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.303→36.104 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2319 0 27 121 2467
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0022405
X-RAY DIFFRACTIONf_angle_d0.4963257
X-RAY DIFFRACTIONf_dihedral_angle_d15.9281438
X-RAY DIFFRACTIONf_chiral_restr0.041349
X-RAY DIFFRACTIONf_plane_restr0.003417
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3031-2.48090.35821070.27242779X-RAY DIFFRACTION90
2.4809-2.73050.29071490.25592900X-RAY DIFFRACTION95
2.7305-3.12540.26511420.20832974X-RAY DIFFRACTION96
3.1254-3.93690.25231560.20532930X-RAY DIFFRACTION95
3.9369-36.10830.21661500.19363036X-RAY DIFFRACTION97

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