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- PDB-7jyo: JAK2 JH2 in complex with JAK064 -

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Basic information

Entry
Database: PDB / ID: 7jyo
TitleJAK2 JH2 in complex with JAK064
ComponentsTyrosine-protein kinase JAK2
KeywordsTRANSFERASE/INHIBITOR / PSEUDOKINASE DOMAIN / INHIBITOR / COMPLEX / TRANSFERASE / TRANSFERASE-INHIBITOR COMPLEX
Function / homology
Function and homology information


interleukin-35-mediated signaling pathway / nuclear receptor-mediated mineralocorticoid signaling pathway / 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 / interleukin-12 receptor complex / histone H3Y41 kinase activity / interleukin-23 receptor complex ...interleukin-35-mediated signaling pathway / nuclear receptor-mediated mineralocorticoid signaling pathway / 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 / interleukin-12 receptor complex / histone H3Y41 kinase activity / interleukin-23 receptor complex / 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 / interleukin-23-mediated signaling pathway / activation of Janus kinase activity / response to interleukin-12 / Erythropoietin activates Phospholipase C gamma (PLCG) / Interleukin-23 signaling / positive regulation of leukocyte proliferation / positive regulation of T-helper 17 type immune response / interleukin-12-mediated signaling pathway / type 1 angiotensin receptor binding / positive regulation of NK T cell proliferation / post-embryonic hemopoiesis / erythropoietin-mediated signaling pathway / Interleukin-12 signaling / IL-6-type cytokine receptor ligand interactions / Interleukin-27 signaling / Interleukin-35 Signalling / positive regulation of MHC class II biosynthetic process / acetylcholine receptor binding / positive regulation of natural killer cell proliferation / positive regulation of platelet activation / growth hormone receptor binding / regulation of nitric oxide biosynthetic process / cellular response to interleukin-3 / interleukin-3-mediated signaling pathway / positive regulation of platelet aggregation / Signaling by Leptin / positive regulation of epithelial cell apoptotic process / regulation of receptor signaling pathway via JAK-STAT / positive regulation of cell-substrate adhesion / extrinsic component of cytoplasmic side of plasma membrane / axon regeneration / extrinsic component of plasma membrane / response to hydroperoxide / Interleukin-20 family signaling / growth hormone receptor signaling pathway / Interleukin-6 signaling / negative regulation of cardiac muscle cell apoptotic process / positive regulation of tyrosine phosphorylation of STAT protein / intrinsic apoptotic signaling pathway in response to oxidative stress / negative regulation of cell-cell adhesion / peptide hormone receptor binding / IFNG signaling activates MAPKs / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / MAPK3 (ERK1) activation / interleukin-6-mediated signaling pathway / enzyme-linked receptor protein signaling pathway / MAPK1 (ERK2) activation / Prolactin receptor signaling / positive regulation of interleukin-17 production / response to amine / signaling receptor activator activity / mesoderm development / platelet-derived growth factor receptor signaling pathway / insulin receptor substrate binding / response to tumor necrosis factor / Interleukin-3, Interleukin-5 and GM-CSF signaling / positive regulation of SMAD protein signal transduction / growth hormone receptor signaling pathway via JAK-STAT / cell surface receptor signaling pathway via JAK-STAT / type II interferon-mediated signaling pathway / Interleukin receptor SHC signaling / phosphatidylinositol 3-kinase binding / Regulation of IFNG signaling / Growth hormone receptor signaling / Signaling by CSF3 (G-CSF) / Erythropoietin activates RAS / positive regulation of T cell proliferation / tumor necrosis factor-mediated signaling pathway / positive regulation of vascular associated smooth muscle cell proliferation / extrinsic apoptotic signaling pathway / actin filament polymerization / negative regulation of cytokine production involved in inflammatory response / post-translational protein modification / cellular response to dexamethasone stimulus / SH2 domain binding / lipopolysaccharide-mediated signaling pathway / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / erythrocyte differentiation / positive regulation of interleukin-1 beta production / positive regulation of apoptotic signaling pathway / endosome lumen / positive regulation of receptor signaling pathway via JAK-STAT
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 / : / SH2 domain / Jak1 pleckstrin homology-like domain / FERM F2 acyl-CoA binding protein-like domain / FERM F1 ubiquitin-like 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. / Tyrosine-protein kinase, active site / PH-like domain superfamily / 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-VPS / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.16127225177 Å
AuthorsPuleo, D.E. / Krimmer, S.G. / Newton, A.S. / Schlessinger, J. / Jorgensen, W.L.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GMO32136 United States
CitationJournal: Tetrahedron Lett. / Year: 2021
Title: Indoloxytriazines as binding molecules for the JAK2 JH2 pseudokinase domain and its V617F variant
Authors: Newton, A.S. / Liosi, M.E. / Henry, S.P. / Deiana, L. / Faver, J.C. / Krimmer, S.G. / Puleo, D.E. / Schlessinger, J. / Jorgensen, W.L.
History
DepositionAug 31, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 14, 2021Provider: repository / Type: Initial release
Revision 1.1Aug 4, 2021Group: 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.pdbx_database_id_DOI / _citation.title / _citation.year
Revision 1.2Oct 18, 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

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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)33,5613
Polymers33,1211
Non-polymers4402
Water1,29772
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)44.568, 57.375, 61.071
Angle α, β, γ (deg.)90.000, 111.004, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,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-VPS / 3-({4-amino-6-[(4-cyanophenyl)amino]-1,3,5-triazin-2-yl}oxy)benzoic acid


Mass: 348.316 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H12N6O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 72 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.32 Å3/Da / Density % sol: 47 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion
Details: 0.1M TRIS, PH 8.0 0.2M SODIUM ACETATE, 0.001 M TCEP, 12-24% PEG 4,000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.54 Å
DetectorType: DECTRIS PILATUS 200K / Detector: PIXEL / Date: May 12, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.16→50 Å / Num. obs: 15316 / % possible obs: 98.5 % / Redundancy: 3 % / Biso Wilson estimate: 24.5398381888 Å2 / CC1/2: 0.9787 / Rpim(I) all: 0.038 / Rrim(I) all: 0.068 / Rsym value: 0.057 / Net I/σ(I): 15.2
Reflection shellResolution: 2.16→2.24 Å / Redundancy: 2.1 % / Mean I/σ(I) obs: 2.95 / Num. unique obs: 1383 / CC1/2: 0.93 / Rpim(I) all: 0.143 / Rrim(I) all: 0.233 / Rsym value: 0.183 / % possible all: 89.5

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Processing

Software
NameVersionClassification
PHENIX1.11.1_2575refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5usz

5usz


Resolution: 2.16127225177→40.4417155743 Å / SU ML: 0.251661072555 / Cross valid method: FREE R-VALUE / σ(F): 1.33647065844 / Phase error: 26.6186849724
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.246396242352 751 4.90881756978 %
Rwork0.1850969384 14548 -
obs0.188225496472 15299 98.322622108 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 29.7219421899 Å2
Refinement stepCycle: LAST / Resolution: 2.16127225177→40.4417155743 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2034 0 32 72 2138
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.006535866754722113
X-RAY DIFFRACTIONf_angle_d0.805325344722883
X-RAY DIFFRACTIONf_chiral_restr0.0507138756431329
X-RAY DIFFRACTIONf_plane_restr0.00539898526556375
X-RAY DIFFRACTIONf_dihedral_angle_d14.92217869421243
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1613-2.32810.2633666093421430.199310107722724X-RAY DIFFRACTION92.0976549952
2.3281-2.56240.2707970406991280.2054331893612930X-RAY DIFFRACTION99.8693664272
2.5624-2.93310.2707150002831610.2082445938512952X-RAY DIFFRACTION100
2.9331-3.6950.2881534039051460.1899345974512949X-RAY DIFFRACTION100
3.695-40.44171557430.2046276999671730.1627831625222993X-RAY DIFFRACTION99.7165354331

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