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- PDB-5ut6: JAK2 JH2 in complex with a diaminopyrimidine -

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Basic information

Entry
Database: PDB / ID: 5ut6
TitleJAK2 JH2 in complex with a diaminopyrimidine
ComponentsTyrosine-protein kinase JAK2
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Pseudokinase Domain / 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 / 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-8MY / ACETATE ION / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.645 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: ACS Med Chem Lett / Year: 2017
Title: JAK2 JH2 Fluorescence Polarization Assay and Crystal Structures for Complexes with Three Small Molecules.
Authors: Newton, A.S. / Deiana, L. / Puleo, D.E. / Cisneros, J.A. / Cutrona, K.J. / Schlessinger, J. / Jorgensen, W.L.
History
DepositionFeb 14, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 7, 2017Provider: repository / Type: Initial release
Revision 1.1Jul 5, 2017Group: Database references / Category: citation
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Sep 13, 2017Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Jan 1, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Oct 4, 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

Downloads & links

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Assembly

Deposited unit
A: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,0269
Polymers33,1211
Non-polymers9058
Water5,044280
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)44.371, 57.642, 60.682
Angle α, β, γ (deg.)90.00, 110.24, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 1 molecules A

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


Mass: 33120.961 Da / Num. of mol.: 1 / Fragment: UNP residues 536-812 / 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

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Non-polymers , 5 types, 288 molecules

#2: Chemical ChemComp-8MY / 4-({4-amino-6-[3-(hydroxymethyl)-1H-pyrazol-1-yl]pyrimidin-2-yl}amino)benzonitrile


Mass: 307.310 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H13N7O
#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: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 280 / Source method: isolated from a natural source / Formula: H2O

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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: 2.2 Å3/Da / Density % sol: 44.05 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 8
Details: 0.1M Tris, pH 8.0 0.2M Sodium acetate 12-20% PEG 4,000
PH range: 7.5-8.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.98 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Mar 30, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 1.64→41.6 Å / Num. obs: 34041 / % possible obs: 97.1 % / Redundancy: 3.4 % / Rsym value: 0.053 / Net I/σ(I): 11.7
Reflection shellResolution: 1.64→1.7 Å / Redundancy: 1.4 % / Mean I/σ(I) obs: 0.82 / Rsym value: 0.714 / % possible all: 73.1

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Processing

Software
NameVersionClassification
PHENIX1.11.1_2575refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4FVP

4fvp


Resolution: 1.645→41.6 Å / SU ML: 0.2 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 22.66
RfactorNum. reflection% reflection
Rfree0.2059 1723 5.07 %
Rwork0.1664 --
obs0.1685 33973 97.15 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.645→41.6 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2105 0 61 281 2447
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0122233
X-RAY DIFFRACTIONf_angle_d1.1913031
X-RAY DIFFRACTIONf_dihedral_angle_d15.3271329
X-RAY DIFFRACTIONf_chiral_restr0.071337
X-RAY DIFFRACTIONf_plane_restr0.009390
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.6451-1.69350.35441000.34561880X-RAY DIFFRACTION68
1.6935-1.74820.33461350.29232692X-RAY DIFFRACTION98
1.7482-1.81060.2591540.23062738X-RAY DIFFRACTION100
1.8106-1.88310.22661530.20392739X-RAY DIFFRACTION100
1.8831-1.96890.22411300.17932788X-RAY DIFFRACTION100
1.9689-2.07270.20721350.16022765X-RAY DIFFRACTION100
2.0727-2.20250.20251360.15622800X-RAY DIFFRACTION100
2.2025-2.37260.20161490.15922735X-RAY DIFFRACTION100
2.3726-2.61130.21451460.16222786X-RAY DIFFRACTION100
2.6113-2.98920.2031650.15892745X-RAY DIFFRACTION100
2.9892-3.7660.18461700.14242747X-RAY DIFFRACTION100
3.766-56.96950.17481500.14222835X-RAY DIFFRACTION99
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
15.0302-1.3374-0.66633.60850.62342.4678-0.13360.02690.27440.30480.218-0.1701-0.12630.1885-0.08620.17940.0092-0.05190.1561-0.04190.0808-23.859122.125884.3245
21.4697-1.79560.07265.8827-1.28641.9051-0.0014-0.00420.05540.0761-0.0044-0.123-0.08920.17240.00940.1429-0.0256-0.01750.1288-0.03150.0973-21.587921.76179.8259
34.3640.74615.11433.50762.07366.9746-0.024-0.21730.21360.1313-0.0735-0.2385-0.0574-0.15930.09950.107-0.01760.01160.12050.03510.1718-19.780721.413175.3683
42.80461.07072.34074.00522.34334.7943-0.0696-0.0596-0.13040.001-0.1930.60330.0921-0.45870.19670.1175-0.00740.06990.195-0.03250.2229-34.307211.267672.8592
53.7649-0.6722-0.31393.1967-0.00712.6340.04160.1970.0934-0.1232-0.06710.2336-0.0433-0.25070.01580.09950.0133-0.0190.0899-0.00040.0893-28.11710.367563.1425
62.34690.02331.28152.28870.29942.3045-0.0569-0.1623-0.00170.13890.0043-0.20760.09220.16580.05030.10530.0268-0.0060.11540.00930.0987-17.3477-0.33472.6028
73.2375-0.16471.57862.773-1.15586.2776-0.0863-0.1086-0.19170.0924-0.10340.14560.2891-0.00240.15870.18020.00560.06120.0575-00.1484-25.1117-10.572.2012
84.1927-1.30861.00365.8766-1.69734.86370.04980.23540.0067-0.3075-0.17070.0379-0.10030.13610.10340.14160.01970.01170.0958-0.02760.0429-20.2087-2.99257.5929
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 537 through 556 )
2X-RAY DIFFRACTION2chain 'A' and (resid 557 through 603 )
3X-RAY DIFFRACTION3chain 'A' and (resid 604 through 622 )
4X-RAY DIFFRACTION4chain 'A' and (resid 623 through 646 )
5X-RAY DIFFRACTION5chain 'A' and (resid 647 through 697 )
6X-RAY DIFFRACTION6chain 'A' and (resid 698 through 748 )
7X-RAY DIFFRACTION7chain 'A' and (resid 749 through 780 )
8X-RAY DIFFRACTION8chain 'A' and (resid 781 through 808 )

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