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- PDB-6m9h: JAK2 JH2 in complex with diaminopyrimidine JAK040 -

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Basic information

Entry
Database: PDB / ID: 6m9h
TitleJAK2 JH2 in complex with diaminopyrimidine JAK040
ComponentsTyrosine-protein kinase JAK2
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / 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 / : / 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 / granulocyte macrophage colony-stimulating factor receptor complex ...interleukin-35-mediated signaling pathway / nuclear receptor-mediated mineralocorticoid signaling pathway / histone H3Y41 kinase activity / : / 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 / granulocyte macrophage colony-stimulating factor receptor complex / granulocyte-macrophage colony-stimulating factor signaling pathway / Signaling by Erythropoietin / collagen-activated signaling pathway / interleukin-23-mediated signaling pathway / interleukin-12 receptor binding / Erythropoietin activates STAT5 / response to interleukin-12 / interleukin-5-mediated signaling pathway / Erythropoietin activates Phospholipase C gamma (PLCG) / positive regulation of leukocyte proliferation / post-embryonic hemopoiesis / erythropoietin-mediated signaling pathway / interleukin-12 receptor complex / activation of Janus kinase activity / tyrosine phosphorylation of STAT protein / interleukin-23 receptor complex / Interleukin-23 signaling / positive regulation of platelet aggregation / positive regulation of T-helper 17 type immune response / positive regulation of MHC class II biosynthetic process / interleukin-12-mediated signaling pathway / acetylcholine receptor binding / type 1 angiotensin receptor binding / positive regulation of NK T cell proliferation / positive regulation of platelet activation / interleukin-3-mediated signaling pathway / cellular response to interleukin-3 / regulation of nitric oxide biosynthetic process / Signaling by Leptin / Interleukin-12 signaling / Interleukin-27 signaling / IL-6-type cytokine receptor ligand interactions / Interleukin-35 Signalling / positive regulation of signaling receptor activity / positive regulation of epithelial cell apoptotic process / positive regulation of natural killer cell proliferation / positive regulation of cell-substrate adhesion / regulation of receptor signaling pathway via JAK-STAT / growth hormone receptor binding / growth hormone receptor signaling pathway / axon regeneration / response to hydroperoxide / negative regulation of cardiac muscle cell apoptotic process / intrinsic apoptotic signaling pathway in response to oxidative stress / extrinsic component of plasma membrane / peptide hormone receptor binding / Interleukin-20 family signaling / IFNG signaling activates MAPKs / Interleukin-6 signaling / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / negative regulation of cell-cell adhesion / interleukin-6-mediated signaling pathway / enzyme-linked receptor protein signaling pathway / Prolactin receptor signaling / MAPK3 (ERK1) activation / response to amine / negative regulation of DNA binding / extrinsic component of cytoplasmic side of plasma membrane / mesoderm development / positive regulation of nitric-oxide synthase biosynthetic process / positive regulation of interleukin-17 production / MAPK1 (ERK2) activation / positive regulation of SMAD protein signal transduction / cell surface receptor signaling pathway via JAK-STAT / platelet-derived growth factor receptor signaling pathway / insulin receptor substrate binding / Interleukin-3, Interleukin-5 and GM-CSF signaling / type II interferon-mediated signaling pathway / growth hormone receptor signaling pathway via JAK-STAT / Interleukin receptor SHC signaling / response to tumor necrosis factor / phosphatidylinositol 3-kinase binding / Regulation of IFNG signaling / Erythropoietin activates RAS / Signaling by CSF3 (G-CSF) / Growth hormone receptor signaling / positive regulation of T cell proliferation / positive regulation of tyrosine phosphorylation of STAT protein / positive regulation of vascular associated smooth muscle cell proliferation / tumor necrosis factor-mediated signaling pathway / extrinsic apoptotic signaling pathway / post-translational protein modification / actin filament polymerization / SH2 domain binding / cellular response to dexamethasone stimulus / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / erythrocyte differentiation / positive regulation of interleukin-1 beta production / endosome lumen / positive regulation of cell differentiation
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 / SH2 domain / 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 / SH2 domain / 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 / 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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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-J9D / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.79 Å
AuthorsPuleo, D.E. / Schlessinger, J. / Jorgensen, W.L.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM007324 United States
Other privateYG-003-13 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM32136 United States
CitationJournal: To Be Published
Title: JAK2 JH2 Binders
Authors: Puleo, D.E. / Schlessinger, J.
History
DepositionAug 23, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 5, 2018Provider: repository / Type: Initial release
Revision 1.1Nov 21, 2018Group: Author supporting evidence / Data collection / Structure summary
Category: audit_author / pdbx_audit_support
Revision 1.2Jan 1, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Mar 13, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
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)33,6134
Polymers33,1211
Non-polymers4923
Water4,846269
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area370 Å2
ΔGint-1 kcal/mol
Surface area12930 Å2
MethodPISA
Unit cell
Length a, b, c (Å)44.298, 57.600, 60.691
Angle α, β, γ (deg.)90.00, 110.17, 90.00
Int Tables number4
Space group name H-MP1211

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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-J9D / 4-({4-amino-6-[4-(2-hydroxyethyl)-1H-imidazol-1-yl]pyrimidin-2-yl}amino)benzonitrile


Mass: 321.337 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H15N7O / 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: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 269 / 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: 2.19 Å3/Da / Density % sol: 43.95 %
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: 1.79→56.971 Å / Num. obs: 27116 / % possible obs: 98 % / Redundancy: 3.7 % / Rmerge(I) obs: 1.311 / Net I/σ(I): 14.25
Reflection shellResolution: 1.79→1.85 Å / Rmerge(I) obs: 7.879 / Num. unique all: 9535

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Processing

Software
NameClassification
PHENIXrefinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementResolution: 1.79→56.971 Å / SU ML: 0.2 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 22.37
RfactorNum. reflection% reflection
Rfree0.2063 1344 5.05 %
Rwork0.1706 --
obs0.1725 26601 98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.79→56.971 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2130 0 34 269 2433
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082218
X-RAY DIFFRACTIONf_angle_d0.9283013
X-RAY DIFFRACTIONf_dihedral_angle_d15.8421320
X-RAY DIFFRACTIONf_chiral_restr0.058336
X-RAY DIFFRACTIONf_plane_restr0.006390
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.79-1.8540.33831290.29662507X-RAY DIFFRACTION98
1.854-1.92830.3231030.25392545X-RAY DIFFRACTION98
1.9283-2.0160.21931300.20112510X-RAY DIFFRACTION98
2.016-2.12230.21251240.18372519X-RAY DIFFRACTION98
2.1223-2.25530.19331320.1672469X-RAY DIFFRACTION97
2.2553-2.42940.19521450.16512483X-RAY DIFFRACTION97
2.4294-2.67390.21211470.17082512X-RAY DIFFRACTION98
2.6739-3.06080.21021260.1712541X-RAY DIFFRACTION98
3.0608-3.85620.20711580.1462574X-RAY DIFFRACTION99
3.8562-56.99970.16711500.14482597X-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)
14.2008-0.94360.22576.14-0.59721.8176-0.03260.12090.26820.27450.014-0.1671-0.12080.34780.00420.2518-0.007-0.0250.2148-0.040.0646-2.625922.206727.1996
20.6638-0.3445-0.40013.3863-0.75911.7836-0.0128-0.07440.05430.09520.0289-0.1362-0.11650.1843-0.02140.2348-0.0128-0.01050.165-0.02290.1491-0.681221.998623.2476
33.0026-0.21964.15691.968-0.00978.9867-0.0612-0.15010.18940.0353-0.0617-0.2815-0.37160.20850.22040.1613-0.04040.00810.17740.01890.19161.197321.407418.3703
42.03930.41091.6313.73581.86815.1361-0.0537-0.0211-0.07750.0963-0.18850.69130.0702-0.44610.21440.12040.01540.0560.2006-0.02770.2517-13.383711.342115.7874
53.9858-0.3177-0.51383.2948-0.03672.49880.08820.21370.1083-0.1561-0.11920.2279-0.0446-0.22820.02160.13540.0158-0.01370.0947-0.00430.0867-7.146210.4166.1998
62.7352-0.32791.08093.02870.59972.8301-0.0706-0.2478-0.07210.42570.0677-0.3670.05050.1990.04650.16090.0471-0.02010.18570.00180.11584.26331.182821.1328
71.4633-0.04210.34332.99530.05742.3527-0.0739-0.07520.11480.0045-0.013-0.2520.1330.26340.06740.17580.03190.0080.11830.00730.09283.2922-1.403111.5155
82.24720.1012-0.18882.5983-0.6523.9897-0.1098-0.1348-0.21760.0951-0.12160.04880.38870.10650.16780.23190.02720.06330.0820.00480.1624-3.8585-10.690715.3291
92.7757-0.328-0.27983.1922-0.71133.60830.07850.1884-0.0709-0.2878-0.16030.0399-0.06230.10130.13440.22280.03110.02080.1244-0.020.0540.5253-2.71510.5588
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 536 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 720 )
7X-RAY DIFFRACTION7chain 'A' and (resid 721 through 748 )
8X-RAY DIFFRACTION8chain 'A' and (resid 749 through 780 )
9X-RAY DIFFRACTION9chain 'A' and (resid 781 through 808 )

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