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- PDB-5usy: JAK2 JH1 in complex with JNJ-7706621 -

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Basic information

Entry
Database: PDB / ID: 5usy
TitleJAK2 JH1 in complex with JNJ-7706621
ComponentsTyrosine-protein kinase JAK2
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Kinase 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 / extrinsic component of cytoplasmic side of plasma membrane / response to hydroperoxide / 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) / enzyme-linked receptor protein signaling pathway / peptide hormone receptor binding / 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 interleukin-17 production / positive regulation of natural killer cell proliferation / response to tumor necrosis factor / signaling receptor activator activity / Interleukin-3, Interleukin-5 and GM-CSF signaling / insulin receptor substrate binding / positive regulation of SMAD protein signal transduction / 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 / 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 / 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 / tumor necrosis factor-mediated signaling pathway / erythrocyte differentiation / 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 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: Identification and Characterization of JAK2 Pseudokinase Domain Small Molecule Binders.
Authors: Puleo, D.E. / Kucera, K. / Hammaren, H.M. / Ungureanu, D. / Newton, A.S. / Silvennoinen, O. / Jorgensen, W.L. / Schlessinger, J.
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 1.3Sep 27, 2017Group: Data collection / Category: diffrn_detector / Item: _diffrn_detector.detector
Revision 1.4Jan 1, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.5Oct 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
Revision 1.6Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2
Revision 1.7Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Tyrosine-protein kinase JAK2
B: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,34212
Polymers74,7972
Non-polymers1,54510
Water11,836657
1
A: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,1696
Polymers37,3981
Non-polymers7715
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,1736
Polymers37,3981
Non-polymers7755
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)137.017, 68.965, 100.567
Angle α, β, γ (deg.)90.00, 127.16, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-1449-

HOH

21B-1580-

HOH

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Components

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


Mass: 37398.402 Da / Num. of mol.: 2 / Fragment: UNP residues 840-1132
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.: 2 / Source method: obtained synthetically / Formula: C15H12F2N6O3S
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 657 / 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: 2.52 Å3/Da / Density % sol: 51.24 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.6
Details: 0.1M Sodium citrate, pH 5.6 0.2 M Ammonium sulfate 30% PEG 4,000
PH range: 5.4-5.8

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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: Jan 31, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2→37.619 Å / Num. obs: 50325 / % possible obs: 99.3 % / Redundancy: 3 % / Rsym value: 0.091 / Net I/σ(I): 9.6
Reflection shellResolution: 2→2.07 Å / Redundancy: 2.8 % / Mean I/σ(I) obs: 2.52 / Rsym value: 0.251 / % possible all: 96.4

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Processing

Software
NameVersionClassification
PHENIX1.11.1_2575refinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2B7A

2b7a


Resolution: 2→37.619 Å / SU ML: 0.18 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 22.15
RfactorNum. reflection% reflection
Rfree0.2158 2524 5.02 %
Rwork0.1757 --
obs0.1777 50232 99.02 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2→37.619 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4667 0 97 665 5429
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0134882
X-RAY DIFFRACTIONf_angle_d1.2716608
X-RAY DIFFRACTIONf_dihedral_angle_d19.172922
X-RAY DIFFRACTIONf_chiral_restr0.074699
X-RAY DIFFRACTIONf_plane_restr0.008842
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.999-2.03740.23581410.18232478X-RAY DIFFRACTION93
2.0374-2.0790.26231440.18452592X-RAY DIFFRACTION98
2.079-2.12420.21791280.1732619X-RAY DIFFRACTION99
2.1242-2.17360.21751270.16962679X-RAY DIFFRACTION100
2.1736-2.2280.20491520.1632630X-RAY DIFFRACTION100
2.228-2.28820.25151350.19792643X-RAY DIFFRACTION100
2.2882-2.35550.23991360.18372668X-RAY DIFFRACTION100
2.3555-2.43150.21291520.16672644X-RAY DIFFRACTION100
2.4315-2.51840.21911270.18412701X-RAY DIFFRACTION100
2.5184-2.61920.23681550.18032631X-RAY DIFFRACTION100
2.6192-2.73840.23321470.19422692X-RAY DIFFRACTION100
2.7384-2.88270.22381320.20082635X-RAY DIFFRACTION99
2.8827-3.06330.33411280.22092684X-RAY DIFFRACTION100
3.0633-3.29960.1821490.16622667X-RAY DIFFRACTION100
3.2996-3.63150.18681390.15782695X-RAY DIFFRACTION100
3.6315-4.15640.18821370.15282670X-RAY DIFFRACTION99
4.1564-5.23430.20061380.15582690X-RAY DIFFRACTION99
5.2343-37.62610.19541570.19262690X-RAY DIFFRACTION98
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)
11.96560.3692-1.04340.7175-0.59852.04410.083-0.01530.0608-0.0319-0.0515-0.03140.00690.1455-0.01530.08060.0108-0.00280.0617-0.0150.0962-20.272626.159894.7587
21.2677-0.069-0.38522.38840.61561.6558-0.02340.015-0.0326-0.00660.02840.02180.03180.025-0.00490.0456-0.0005-0.0150.08090.0040.0755-36.06779.496699.9704
31.64690.3738-0.5870.9279-0.70651.53160.0110.09490.0627-0.1044-0.0198-0.0908-0.02510.14730.01120.0777-0.00990.00060.0995-0.01180.10299.323126.228255.093
41.06310.13610.212.24150.35381.47160.02110.0777-0.0198-0.06670.02910.07740.0341-0.0237-0.03820.0293-0.00690.00660.08880.00040.0795-6.55149.46359.2067
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 840 through 992 )
2X-RAY DIFFRACTION2chain 'A' and (resid 993 through 1130 )
3X-RAY DIFFRACTION3chain 'B' and (resid 840 through 992 )
4X-RAY DIFFRACTION4chain 'B' and (resid 993 through 1130 )

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