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

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Basic information

Entry
Database: PDB / ID: 6wtp
TitleHuman JAK2 JH1 domain in complex with PROTAC-intermediate linker handle 3
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 epithelial cell apoptotic process / axon regeneration / growth hormone receptor signaling pathway / peptide hormone receptor binding / intrinsic apoptotic signaling pathway in response to oxidative stress / IFNG signaling activates MAPKs / extrinsic component of plasma membrane / positive regulation of natural killer cell proliferation / Interleukin-20 family signaling / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / negative regulation of cell-cell adhesion / Interleukin-6 signaling / enzyme-linked receptor protein signaling pathway / interleukin-6-mediated signaling pathway / Prolactin receptor signaling / positive regulation of interleukin-17 production / negative regulation of DNA binding / MAPK3 (ERK1) activation / response to amine / positive regulation of nitric-oxide synthase biosynthetic process / MAPK1 (ERK2) activation / positive regulation of SMAD protein signal transduction / mesoderm development / 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 apoptotic signaling pathway / positive regulation of tyrosine phosphorylation of STAT protein / positive regulation of vascular associated smooth muscle cell proliferation / tumor necrosis factor-mediated signaling pathway / extrinsic component of cytoplasmic side of plasma membrane / 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 / 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-U8P / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 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)37,0673
Polymers36,4121
Non-polymers6552
Water37821
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)80.517, 80.517, 85.165
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number152
Space group name H-MP3121

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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-U8P / tert-butyl 4-[(4-{1-[3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl]-1H-pyrazol-4-yl}-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]benzoate


Mass: 562.643 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H30N8O4S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


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


Mass: 18.015 Da / Num. of mol.: 21 / 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: 2.19 Å3/Da / Density % sol: 43.8 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 5
Details: 0.1 M SODIUM CITRATE PH 6.0, 27% PEG 8000 AND 0.2 M AMMONIUM ACETATE. REMARK 280 6.0, 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: 21-ID-D / 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: 2.5→36.39 Å / Num. obs: 11406 / % possible obs: 99.8 % / Redundancy: 6.5 % / CC1/2: 0.941 / Rmerge(I) obs: 0.11 / Rpim(I) all: 0.048 / Rrim(I) all: 0.121 / Net I/σ(I): 8.7
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.5-2.576.71.01654738130.8710.4181.11.899.8
11.18-36.395.50.0938531560.7150.0560.11118.298.2

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Processing

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

5usy


Resolution: 2.5→36.39 Å / SU ML: 0.38 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 34.67 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.288 567 5 %
Rwork0.2377 10779 -
obs0.2402 11346 99.38 %
Solvent computationShrinkage radii: 1.1 Å / VDW probe radii: 1.2 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 170.76 Å2 / Biso mean: 72.0744 Å2 / Biso min: 30.23 Å2
Refinement stepCycle: final / Resolution: 2.5→36.39 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2045 0 46 21 2112
Biso mean--73.88 59.5 -
Num. residues----276
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 4

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.5-2.750.37841400.31422633277399
2.75-3.150.36041370.27442652278999
3.15-3.970.24841460.229926912837100
3.97-36.40.27771440.22022803294799
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)
14.49191.94-6.2795.7073-1.48669.42410.61091.21243.48830.50491.0311-0.49160.0332-0.7128-1.34150.506-0.0822-0.02850.7302-0.01981.351412.400915.33917.6308
25.9968-0.6327-1.26566.0971-3.50052.24530.4389-0.2556-0.32770.62590.46312.96550.0091-0.8062-0.45710.5075-0.04450.06380.8092-0.01111.60528.236213.494312.651
34.1381-0.24351.70294.56-1.67411.15870.2714-0.58650.0550.1870.17041.0638-0.0378-0.2963-0.31020.448-0.13050.12080.7102-0.08850.808718.84376.331112.631
49.1242-2.03515.20624.8916-5.83758.37960.00050.21191.70691.73530.15950.6361-0.2056-0.4860.65850.62830.12380.09250.4399-0.20010.559134.189425.24411.6836
56.34271.9052.16586.65610.45522.30.4875-0.6771-0.24070.5464-0.55610.45960.3646-0.14260.05240.5319-0.08760.03340.4792-0.03410.28932.81729.713714.9145
64.00422.3376-1.85136.7673-1.6695.0893-0.0344-0.1573-0.6851-0.89020.04880.83161.5394-0.0511-0.20230.6254-0.0341-0.13750.4001-0.02180.606131.2198-1.74353.3866
76.60592.90130.68034.1087-0.99794.87520.13640.2549-0.80270.2883-0.0411-0.08290.45950.3894-0.24020.55120.0376-0.03240.3625-0.03280.37439.58714.34024.1537
83.6152-0.5328-0.69958.7716-0.48585.9813-0.03140.3649-0.1339-0.90760.0454-0.1264-0.17570.6203-0.00830.60780.00160.00020.4398-0.02440.340644.024313.3034-4.551
97.4342.0631-0.37026.6587-2.85487.44460.5225-0.3591-1.0380.527-0.7979-1.57860.61440.28510.19210.48750.1034-0.11370.40960.04520.566148.48564.22328.1261
106.76574.22011.53543.74192.80693.26220.4626-0.14480.15040.93860.0117-0.13690.7660.7478-0.50610.7976-0.0648-0.12170.66420.02960.387846.112910.837421.5221
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 844 through 867 )A844 - 867
2X-RAY DIFFRACTION2chain 'A' and (resid 868 through 888 )A868 - 888
3X-RAY DIFFRACTION3chain 'A' and (resid 889 through 936 )A889 - 936
4X-RAY DIFFRACTION4chain 'A' and (resid 937 through 949 )A937 - 949
5X-RAY DIFFRACTION5chain 'A' and (resid 950 through 992 )A950 - 992
6X-RAY DIFFRACTION6chain 'A' and (resid 993 through 1022 )A993 - 1022
7X-RAY DIFFRACTION7chain 'A' and (resid 1023 through 1048 )A0
8X-RAY DIFFRACTION8chain 'A' and (resid 1049 through 1095 )A0
9X-RAY DIFFRACTION9chain 'A' and (resid 1096 through 1115 )A0
10X-RAY DIFFRACTION10chain 'A' and (resid 1116 through 1133 )A0

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