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- PDB-5i4n: Crystal Structure of the E596A V617F Mutant JAK2 Pseudokinase Dom... -

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Basic information

Entry
Database: PDB / ID: 5i4n
TitleCrystal Structure of the E596A V617F Mutant JAK2 Pseudokinase Domain Bound to Mg-ATP
ComponentsTyrosine-protein kinase JAK2
KeywordsTRANSFERASE / PSEUDOKINASE / ATP BINDING
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 / histone H3Y41 kinase activity / 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 / 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 / histone H3Y41 kinase activity / 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 / 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 / response to amine / positive regulation of interleukin-17 production / 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 / Regulation of IFNG signaling / phosphatidylinositol 3-kinase binding / Growth hormone receptor signaling / Signaling by CSF3 (G-CSF) / Erythropoietin activates RAS / positive regulation of T cell proliferation / tumor necrosis factor-mediated signaling pathway / extrinsic apoptotic signaling pathway / positive regulation of vascular associated smooth muscle cell proliferation / actin filament polymerization / negative regulation of cytokine production involved in inflammatory response / post-translational protein modification / SH2 domain binding / cellular response to dexamethasone stimulus / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / lipopolysaccharide-mediated signaling pathway / erythrocyte differentiation / positive regulation of apoptotic signaling pathway / positive regulation of interleukin-1 beta production / 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 / 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
ADENOSINE-5'-TRIPHOSPHATE / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.54 Å
AuthorsShiau, A.K. / Motamedi, A.
CitationJournal: Biochem.J. / Year: 2016
Title: Uncoupling JAK2 V617F activation from cytokine-induced signalling by modulation of JH2 alpha C helix.
Authors: Leroy, E. / Dusa, A. / Colau, D. / Motamedi, A. / Cahu, X. / Mouton, C. / Huang, L.J. / Shiau, A.K. / Constantinescu, S.N.
History
DepositionFeb 12, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 13, 2016Provider: repository / Type: Initial release
Revision 1.1Jun 8, 2016Group: Database references
Revision 1.2Sep 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / database_2 / pdbx_initial_refinement_model / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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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)33,8664
Polymers33,2421
Non-polymers6243
Water3,351186
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1270 Å2
ΔGint-12 kcal/mol
Surface area12940 Å2
MethodPISA
Unit cell
Length a, b, c (Å)53.429, 56.965, 114.868
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 33242.164 Da / Num. of mol.: 1 / Mutation: E596A V617F W659A W777A F794H
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: JAK2 / Plasmid: PFASTBAC / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): SF9
References: UniProt: O60674, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE


Mass: 507.181 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / Comment: ATP, energy-carrying molecule*YM
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


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


Mass: 18.015 Da / Num. of mol.: 186 / 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: 2.63 Å3/Da / Density % sol: 53.22 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 8.5 / Details: 0.1 M TRIS, 0.2M SODIUM ACETATE, 22% PEG 4000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-C / Wavelength: 0.9791 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Nov 12, 2014
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9791 Å / Relative weight: 1
ReflectionResolution: 1.54→114.87 Å / Num. obs: 52561 / % possible obs: 99.7 % / Redundancy: 6.3 % / CC1/2: 0.998 / Rmerge(I) obs: 0.063 / Net I/σ(I): 16.4
Reflection shellResolution: 1.54→1.62 Å / Redundancy: 6.1 % / Rmerge(I) obs: 0.94 / Mean I/σ(I) obs: 1.9 / % possible all: 99.7

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Processing

Software
NameVersionClassification
PHENIX1.8.2_1309refinement
XDSdata reduction
Aimless0.1.27data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4FVP

4fvp


Resolution: 1.54→48.445 Å / SU ML: 0.24 / Cross valid method: THROUGHOUT / σ(F): 1.37 / Phase error: 20.58
RfactorNum. reflection% reflection
Rfree0.1929 1991 3.79 %
Rwork0.1736 --
obs0.1743 52484 99.61 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.54→48.445 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2204 0 38 186 2428
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.012302
X-RAY DIFFRACTIONf_angle_d1.3713120
X-RAY DIFFRACTIONf_dihedral_angle_d15.496858
X-RAY DIFFRACTIONf_chiral_restr0.083344
X-RAY DIFFRACTIONf_plane_restr0.007395
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.54-1.57850.41381470.45573542X-RAY DIFFRACTION99
1.5785-1.62120.36891380.36173569X-RAY DIFFRACTION100
1.6212-1.66890.30851330.31523569X-RAY DIFFRACTION100
1.6689-1.72280.2781460.25413558X-RAY DIFFRACTION100
1.7228-1.78440.23471340.20023585X-RAY DIFFRACTION100
1.7844-1.85580.20991320.18393574X-RAY DIFFRACTION100
1.8558-1.94030.20061510.18533556X-RAY DIFFRACTION100
1.9403-2.04260.19291370.16573609X-RAY DIFFRACTION100
2.0426-2.17050.19851430.15863605X-RAY DIFFRACTION100
2.1705-2.33810.16211450.14933595X-RAY DIFFRACTION100
2.3381-2.57340.181460.1633626X-RAY DIFFRACTION100
2.5734-2.94570.20611450.16663636X-RAY DIFFRACTION100
2.9457-3.71110.18521390.16583653X-RAY DIFFRACTION99
3.7111-48.46880.16331550.15113816X-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)
11.52440.77350.0983.945-1.98092.6961-0.1195-0.01670.29820.08590.27320.4791-0.299-0.3084-0.18510.23020.0265-0.03770.24680.0350.2688-16.7003-3.1016.502
21.35011.11240.53424.15041.24411.8790.0503-0.09310.47090.1288-0.15630.2484-0.5649-0.10760.02620.3834-0.025-0.04250.20040.00220.2943-9.8414.0097.9945
33.1140.7314-0.29334.05660.29052.8852-0.0586-0.11470.1424-0.35040.08970.3592-0.1461-0.219-0.09060.21130.0319-0.07520.2344-0.01060.2454-15.6436-3.03067.602
42.71590.24120.97452.1714-0.08412.4042-0.0557-0.28820.1990.06360.1160.3846-0.2131-0.4453-0.02560.1820.038-0.00030.2433-0.00070.2544-16.1947-6.43216.8614
52.7265-1.4705-0.41242.86350.90431.51930.05410.29560.0644-0.398-0.2065-0.21940.15780.22060.16130.22960.01320.0310.24060.02960.18723.0685-17.24926.4137
63.7431-0.9869-2.15672.00060.24323.3848-0.0813-0.2128-0.14970.1611-0.0542-0.09570.20670.1170.09250.1679-0.0219-0.01260.18120.00170.15712.3019-17.22523.1273
70.8111-0.256-0.21262.3732-0.07332.89580.0185-0.06420.062-0.1168-0.0075-0.2258-0.01980.2574-0.00820.13220.0052-0.00740.1577-0.0060.17281.2156-13.110416.1925
81.7244-0.3856-0.05662.7117-1.00871.4939-0.0304-0.0223-0.0848-0.180.18810.38750.2838-0.3762-0.10410.2174-0.0766-0.04320.24030.04720.2361-12.1352-26.855517.7898
92.6478-0.23050.3982.0919-0.34883.3820.0358-0.0763-0.3344-0.30790.0430.08030.5371-0.2013-0.03130.2807-0.053-0.02860.15750.0530.1914-5.5451-34.753521.5225
109.4519-2.0645-1.0095.4859-0.7423.12560.0828-0.13521.13420.32770.0563-0.66730.02170.2895-0.27530.2697-0.0159-0.04630.26830.07870.27272.0676-21.404528.4345
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 537 through 557 )
2X-RAY DIFFRACTION2chain 'A' and (resid 558 through 572 )
3X-RAY DIFFRACTION3chain 'A' and (resid 573 through 587 )
4X-RAY DIFFRACTION4chain 'A' and (resid 588 through 627 )
5X-RAY DIFFRACTION5chain 'A' and (resid 628 through 646 )
6X-RAY DIFFRACTION6chain 'A' and (resid 647 through 666 )
7X-RAY DIFFRACTION7chain 'A' and (resid 667 through 697 )
8X-RAY DIFFRACTION8chain 'A' and (resid 698 through 758 )
9X-RAY DIFFRACTION9chain 'A' and (resid 759 through 797 )
10X-RAY DIFFRACTION10chain 'A' and (resid 798 through 824 )

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