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- PDB-6wtq: Human JAK2 JH1 domain in complex with PROTAC-intermediate linker ... -

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Basic information

Entry
Database: PDB / ID: 6wtq
TitleHuman JAK2 JH1 domain in complex with PROTAC-intermediate linker handle 4
ComponentsTyrosine-protein kinase JAK2
KeywordsTRANSFERASE / Phosphorylation
Function / homology
Function and homology information


interleukin-35-mediated signaling pathway / intracellular mineralocorticoid receptor signaling pathway / histone H3Y41 kinase activity / activation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway / 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 / Signaling by Erythropoietin ...interleukin-35-mediated signaling pathway / intracellular mineralocorticoid receptor signaling pathway / histone H3Y41 kinase activity / activation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway / 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 / Signaling by Erythropoietin / granulocyte macrophage colony-stimulating factor receptor complex / granulocyte-macrophage colony-stimulating factor signaling pathway / interleukin-12 receptor binding / post-embryonic hemopoiesis / collagen-activated signaling pathway / Erythropoietin activates STAT5 / Erythropoietin activates Phospholipase C gamma (PLCG) / interleukin-5-mediated signaling pathway / response to interleukin-12 / positive regulation of leukocyte proliferation / interleukin-12 receptor complex / activation of Janus kinase activity / interleukin-23 receptor complex / positive regulation of platelet aggregation / tyrosine phosphorylation of STAT protein / Interleukin-23 signaling / positive regulation of MHC class II biosynthetic process / positive regulation of T-helper 17 type immune response / positive regulation of platelet activation / type 1 angiotensin receptor binding / positive regulation of NK T cell proliferation / interleukin-12-mediated signaling pathway / interleukin-3-mediated signaling pathway / regulation of nitric oxide biosynthetic process / acetylcholine receptor binding / cellular response to interleukin-3 / Signaling by Leptin / Interleukin-12 signaling / positive regulation of signaling receptor activity / Interleukin-35 Signalling / Interleukin-27 signaling / IL-6-type cytokine receptor ligand interactions / positive regulation of cell-substrate adhesion / response to hydroperoxide / regulation of receptor signaling pathway via JAK-STAT / growth hormone receptor binding / negative regulation of cardiac muscle cell apoptotic process / positive regulation of natural killer cell proliferation / positive regulation of epithelial cell apoptotic process / axon regeneration / growth hormone receptor signaling pathway / peptide hormone receptor binding / intrinsic apoptotic signaling pathway in response to oxidative stress / extrinsic component of plasma membrane / IFNG signaling activates MAPKs / Interleukin-20 family signaling / interleukin-6-mediated signaling pathway / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / negative regulation of cell-cell adhesion / Interleukin-6 signaling / enzyme-linked receptor protein signaling pathway / Prolactin receptor signaling / positive regulation of interleukin-17 production / MAPK3 (ERK1) activation / negative regulation of DNA binding / response to amine / positive regulation of nitric-oxide synthase biosynthetic process / MAPK1 (ERK2) activation / mesoderm development / 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 / growth hormone receptor signaling pathway via JAK-STAT / response to tumor necrosis factor / Interleukin receptor SHC signaling / phosphatidylinositol 3-kinase binding / type II interferon-mediated signaling pathway / Regulation of IFNG signaling / Erythropoietin activates RAS / Growth hormone receptor signaling / extrinsic apoptotic signaling pathway / positive regulation of T cell proliferation / Signaling by CSF3 (G-CSF) / positive regulation of tyrosine phosphorylation of STAT protein / extrinsic component of cytoplasmic side of plasma membrane / positive regulation of vascular associated smooth muscle cell proliferation / tumor necrosis factor-mediated signaling pathway / actin filament polymerization / SH2 domain binding / post-translational protein modification / cellular response to dexamethasone stimulus / erythrocyte differentiation / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / positive regulation of interleukin-1 beta production / positive regulation of apoptotic signaling pathway / caveola / 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 / 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 ...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 / FERM central domain / FERM superfamily, second domain / FERM domain / FERM domain profile. / Band 4.1 domain / Band 4.1 homologues / SH2 domain / 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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-U8J / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.79968475557 Å
AuthorsYu, S. / Nithianantham, S. / Fischer, M.
CitationJournal: Blood / Year: 2021
Title: Degradation of Janus kinases in CRLF2-rearranged acute lymphoblastic leukemia.
Authors: Chang, Y. / Min, J. / Jarusiewicz, J.A. / Actis, M. / Yu-Chen Bradford, S. / Mayasundari, A. / Yang, L. / Chepyala, D. / Alcock, L.J. / Roberts, K.G. / Nithianantham, S. / Maxwell, D. / ...Authors: Chang, Y. / Min, J. / Jarusiewicz, J.A. / Actis, M. / Yu-Chen Bradford, S. / Mayasundari, A. / Yang, L. / Chepyala, D. / Alcock, L.J. / Roberts, K.G. / Nithianantham, S. / Maxwell, D. / Rowland, L. / Larsen, R. / Seth, A. / Goto, H. / Imamura, T. / Akahane, K. / Hansen, B.S. / Pruett-Miller, S.M. / Paietta, E.M. / Litzow, M.R. / Qu, C. / Yang, J.J. / Fischer, M. / Rankovic, Z. / Mullighan, C.G.
History
DepositionMay 3, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 5, 2021Provider: repository / Type: Initial release
Revision 1.1Jun 30, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_id_CSD ..._citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Dec 22, 2021Group: Database references / Category: citation / citation_author / database_2
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID / _citation_author.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.4Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2

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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)36,9724
Polymers36,4121
Non-polymers5603
Water1,08160
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)79.362, 79.362, 84.640
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number152
Space group name H-MP3121
Space group name HallP312"
Symmetry operation#1: x,y,z
#2: -y,x-y,z+1/3
#3: -x+y,-x,z+2/3
#4: x-y,-y,-z+2/3
#5: -x,-x+y,-z+1/3
#6: y,x,-z

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Components

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


Mass: 36412.297 Da / Num. of mol.: 1
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-U8J / N-methyl-4-{[4-(1-propyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}benzamide


Mass: 375.427 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H21N7O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-TRS / 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL / TRIS BUFFER / Tris


Mass: 122.143 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H12NO3 / Comment: pH buffer*YM
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 60 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.11 Å3/Da / Density % sol: 41.79 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 5
Details: 0.1 M SODIUM CITRATE PH 6.5, 27% PEG 8000 AND 0.2 M AMMONIUM ACETATE. REMARK 280 6.5, VAPOR DIFFUSION, HANGING DROP, TEMPERATURE 291K

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Nov 8, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.799→36.04 Å / Num. obs: 29041 / % possible obs: 100 % / Redundancy: 6.9 % / CC1/2: 0.998 / Rmerge(I) obs: 0.077 / Rpim(I) all: 0.031 / Rrim(I) all: 0.083 / Net I/σ(I): 11.7
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
1.799-1.8571.00221140.7380.4071.083100
8.05-36.046.10.0533750.9970.0220.05899.2

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
Aimless0.5.32data scaling
PHASERphasing
PHENIX1.17refinement
PDB_EXTRACT3.25data extraction
xia2data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5USY

5usy


Resolution: 1.79968475557→36.0364456181 Å / SU ML: 0.207470936773 / Cross valid method: THROUGHOUT / σ(F): 1.33541549176 / Phase error: 22.2719531125
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.212725846763 1448 4.99637693661 %
Rwork0.191494477759 27533 -
obs0.192564379918 28981 99.8380873639 %
Solvent computationShrinkage radii: 1.2 Å / VDW probe radii: 1.4 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 43.3181747434 Å2
Refinement stepCycle: LAST / Resolution: 1.79968475557→36.0364456181 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2082 0 40 60 2182
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.006497127309272229
X-RAY DIFFRACTIONf_angle_d0.8362481583473021
X-RAY DIFFRACTIONf_chiral_restr0.0561877253797326
X-RAY DIFFRACTIONf_plane_restr0.00503265167552386
X-RAY DIFFRACTIONf_dihedral_angle_d10.33465198671345
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.7997-1.8640.3103032225631370.2929743664282684X-RAY DIFFRACTION99.5412844037
1.864-1.93860.2894033106131460.2489441330922726X-RAY DIFFRACTION99.7568600208
1.9386-2.02690.2902149147961400.2238364360832724X-RAY DIFFRACTION99.8605299861
2.0269-2.13370.2336331078991410.1886917721952712X-RAY DIFFRACTION99.8949579832
2.1337-2.26740.2270083950051450.1883475318762746X-RAY DIFFRACTION99.9308676115
2.2674-2.44240.2281695596891480.1786484486542721X-RAY DIFFRACTION99.9303378614
2.4424-2.68810.2028000904261420.1797830348672771X-RAY DIFFRACTION99.8971193416
2.6881-3.07690.1893823008471490.1788336092872744X-RAY DIFFRACTION99.79303208
3.0769-3.87590.2196118433611440.1814341477872803X-RAY DIFFRACTION100
3.8759-36.03640.1908108917521560.1937537352632902X-RAY DIFFRACTION99.7716150082
Refinement TLS params.Method: refined / Origin x: 32.902625705 Å / Origin y: -8.81737606413 Å / Origin z: 5.93155049998 Å
111213212223313233
T0.223604385771 Å20.0303402535076 Å20.0225372807877 Å2-0.167605600328 Å2-0.00856739918722 Å2--0.191584952614 Å2
L2.01410533601 °2-0.322114207734 °2-0.510698092772 °2-3.22576570857 °20.508634392649 °2--2.18725446241 °2
S0.137633529384 Å °0.231670975119 Å °0.171774429721 Å °-0.0146152207497 Å °-0.17939285422 Å °0.363539635833 Å °-0.145901510251 Å °-0.208675000963 Å °0.03115567781 Å °
Refinement TLS groupSelection details: all

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