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- PDB-5ut4: JAK2 JH2 in complex with NVP-BSK805 -

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Basic information

Entry
Database: PDB / ID: 5ut4
TitleJAK2 JH2 in complex with NVP-BSK805
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 / : / 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-DQX / 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: 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 1.3Sep 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

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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)33,8745
Polymers33,1211
Non-polymers7534
Water2,000111
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)45.346, 57.155, 60.758
Angle α, β, γ (deg.)90.00, 110.28, 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 / 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
#2: Chemical ChemComp-DQX / 8-[3,5-difluoro-4-(morpholin-4-ylmethyl)phenyl]-2-(1-piperidin-4-yl-1H-pyrazol-4-yl)quinoxaline


Mass: 490.548 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H28F2N6O
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / 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.: 111 / 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: 2.23 Å3/Da / Density % sol: 44.84 %
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: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.54 Å
DetectorType: DECTRIS PILATUS 200K / Detector: PIXEL / Date: May 14, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2→50 Å / Num. obs: 19632 / % possible obs: 98.9 % / Redundancy: 6.7 % / Net I/σ(I): 24.2
Reflection shellHighest resolution: 2 Å / Rsym value: 0.343

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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: 4FVP

4fvp


Resolution: 2→34.123 Å / SU ML: 0.22 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 27.93
RfactorNum. reflection% reflection
Rfree0.2198 922 4.71 %
Rwork0.1786 --
obs0.1804 19596 98.76 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2→34.123 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2078 0 52 111 2241
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0032179
X-RAY DIFFRACTIONf_angle_d0.6622969
X-RAY DIFFRACTIONf_dihedral_angle_d12.2851286
X-RAY DIFFRACTIONf_chiral_restr0.045335
X-RAY DIFFRACTIONf_plane_restr0.004381
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2-2.10540.2941410.24872500X-RAY DIFFRACTION94
2.1054-2.23730.24511310.22662637X-RAY DIFFRACTION98
2.2373-2.410.28791190.19992686X-RAY DIFFRACTION100
2.41-2.65240.24081180.18182698X-RAY DIFFRACTION100
2.6524-3.0360.22061680.1922672X-RAY DIFFRACTION100
3.036-3.82430.21611350.16572709X-RAY DIFFRACTION100
3.8243-34.12750.1741100.15662772X-RAY DIFFRACTION100
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)
14.3138-1.4571-1.61232.68040.72571.3947-0.0204-0.16170.39920.52140.5336-0.4817-0.59620.4972-0.51180.6344-0.0491-0.00150.4888-0.15530.3605-3.254121.352827.9173
21.9074-1.2317-1.05224.4158-0.65412.9250.079-0.04510.28290.14650.1005-0.1675-0.2340.2461-0.15080.39-0.0924-0.01490.3012-0.09660.3415-0.532421.672723.2964
32.41920.3179-0.61664.76720.65276.95970.2337-0.15050.39560.2821-0.15780.3281-0.3278-0.0309-0.01260.24350.0580.05080.2733-0.00590.3488-6.779315.72517.0338
40.6327-0.0875-1.28894.61140.09523.09820.15630.29570.0743-0.1231-0.09570.4157-0.18-0.4172-0.03590.1650.049-0.04630.30370.01690.295-7.216810.68055.9784
53.9409-0.4531-0.33025.35541.48862.8451-0.0297-0.51650.18030.5666-0.0027-0.65190.39480.5930.03950.35790.0884-0.08950.42340.00670.31686.7079-0.159918.9164
62.5225-0.0495-1.235.6014-1.17344.7022-0.2667-0.1836-0.29860.3177-0.02930.01040.63560.16880.21650.320.04960.050.2185-0.00650.2595-3.8635-6.79312.809
73.13640.0282-0.59455.7035-0.76655.14880.05040.2881-0.1252-0.2338-0.20760.19280.10920.09870.17050.27460.04120.00230.2809-0.02610.2284-0.0757-2.57290.2017
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 646 )
4X-RAY DIFFRACTION4chain 'A' and (resid 647 through 697 )
5X-RAY DIFFRACTION5chain 'A' and (resid 698 through 731 )
6X-RAY DIFFRACTION6chain 'A' and (resid 732 through 780 )
7X-RAY DIFFRACTION7chain 'A' and (resid 781 through 809 )

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