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- PDB-9r5z: Crystal structure of JAK3 with GCL258 -

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Basic information

Entry
Database: PDB / ID: 9r5z
TitleCrystal structure of JAK3 with GCL258
ComponentsTyrosine-protein kinase JAK3
KeywordsTRANSFERASE / kinase / covalent inhibitor / lysine / MAPKAPK2
Function / homology
Function and homology information


negative regulation of dendritic cell cytokine production / response to interleukin-9 / response to interleukin-2 / response to interleukin-15 / response to interleukin-4 / negative regulation of T-helper 1 cell differentiation / tyrosine phosphorylation of STAT protein / negative regulation of glycoprotein biosynthetic process / negative regulation of T-helper 17 cell lineage commitment / Interleukin-9 signaling ...negative regulation of dendritic cell cytokine production / response to interleukin-9 / response to interleukin-2 / response to interleukin-15 / response to interleukin-4 / negative regulation of T-helper 1 cell differentiation / tyrosine phosphorylation of STAT protein / negative regulation of glycoprotein biosynthetic process / negative regulation of T-helper 17 cell lineage commitment / Interleukin-9 signaling / Interleukin-21 signaling / interleukin-7-mediated signaling pathway / interleukin-9-mediated signaling pathway / interleukin-4-mediated signaling pathway / negative regulation of T cell activation / interleukin-2-mediated signaling pathway / regulation of T cell apoptotic process / negative regulation of interleukin-12 production / interleukin-15-mediated signaling pathway / Interleukin-15 signaling / negative regulation of thymocyte apoptotic process / growth hormone receptor binding / Interleukin-2 signaling / extrinsic component of cytoplasmic side of plasma membrane / regulation of receptor signaling pathway via JAK-STAT / extrinsic component of plasma membrane / Signaling by ALK / Interleukin-20 family signaling / negative regulation of interleukin-10 production / enzyme-linked receptor protein signaling pathway / T cell homeostasis / growth hormone receptor signaling pathway via JAK-STAT / Interleukin receptor SHC signaling / cell surface receptor signaling pathway via JAK-STAT / Interleukin-7 signaling / B cell differentiation / non-membrane spanning protein tyrosine kinase activity / non-specific protein-tyrosine kinase / cytoplasmic side of plasma membrane / cytokine-mediated signaling pathway / RAF/MAP kinase cascade / protein tyrosine kinase activity / protein phosphatase binding / Interleukin-4 and Interleukin-13 signaling / regulation of apoptotic process / adaptive immune response / Potential therapeutics for SARS / cell differentiation / cytoskeleton / endosome / intracellular signal transduction / innate immune response / ATP binding / plasma membrane / cytosol
Similarity search - Function
Tyrosine-protein kinase, non-receptor Jak3 / 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 ...Tyrosine-protein kinase, non-receptor Jak3 / 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 domain / FERM domain profile. / Band 4.1 domain / Band 4.1 homologues / 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 / 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
: / 1-phenylurea / Tyrosine-protein kinase JAK3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsWang, G.Q. / Chaikuad, A. / Hillebrand, L. / Gehringer, M. / Knapp, S. / Structural Genomics Consortium (SGC)
Funding support Canada, 1items
OrganizationGrant numberCountry
The Structural Genomics Consortium (SGC) Canada
CitationJournal: Rsc Med Chem / Year: 2025
Title: A twist in the tale: shifting from covalent targeting of a tyrosine in JAK3 to a lysine in MK2.
Authors: Hillebrand, L. / Wang, G. / Rasch, A. / Masberg, B. / Chaikuad, A. / Kronenberger, T. / Gunther, E. / Forster, M. / Poso, A. / Lammerhofer, M. / Laufer, S.A. / Knapp, S. / Gehringer, M.
History
DepositionMay 11, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 20, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Tyrosine-protein kinase JAK3
B: Tyrosine-protein kinase JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,9026
Polymers66,8352
Non-polymers1,0674
Water3,927218
1
A: Tyrosine-protein kinase JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,9513
Polymers33,4171
Non-polymers5342
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,9513
Polymers33,4171
Non-polymers5342
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)41.850, 62.540, 101.197
Angle α, β, γ (deg.)90.00, 93.71, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Tyrosine-protein kinase JAK3 / Janus kinase 3 / JAK-3 / Leukocyte janus kinase / L-JAK


Mass: 33417.281 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: JAK3 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P52333, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-A1JJU / 3-(3-cyclohexyl-3,8,10-triazatricyclo[7.3.0.0^{2,6}]dodeca-1,4,6,8,11-pentaen-5-yl)benzenesulfonyl fluoride


Mass: 397.466 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H20FN3O2S
#3: Chemical ChemComp-PHU / 1-phenylurea / Phenylurea


Mass: 136.151 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C7H8N2O
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 218 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 1.98 Å3/Da / Density % sol: 37.79 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop / Details: 31% PEG 3350, 0.2M MgCl2, 0.1M MES pH5.5.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1.00002 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jan 11, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00002 Å / Relative weight: 1
ReflectionResolution: 1.8→41.8 Å / Num. obs: 47991 / % possible obs: 99 % / Redundancy: 7 % / CC1/2: 0.999 / Net I/σ(I): 16.2
Reflection shellResolution: 1.8→1.84 Å / Mean I/σ(I) obs: 2.9 / Num. unique obs: 2873 / CC1/2: 0.885

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Processing

Software
NameVersionClassification
REFMAC5.8.0425refinement
PDB_EXTRACTdata extraction
XDSdata reduction
XDSdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.8→41.8 Å / Cor.coef. Fo:Fc: 0.941 / Cor.coef. Fo:Fc free: 0.917 / SU B: 3.694 / SU ML: 0.117 / Cross valid method: THROUGHOUT / ESU R: 0.174 / ESU R Free: 0.166 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.28935 2392 5 %RANDOM
Rwork0.23595 ---
obs0.23868 45581 98.94 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 30.323 Å2
Baniso -1Baniso -2Baniso -3
1--1.26 Å20 Å2-0.28 Å2
2--1.41 Å20 Å2
3----0.11 Å2
Refinement stepCycle: 1 / Resolution: 1.8→41.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4168 0 76 218 4462
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0124341
X-RAY DIFFRACTIONr_bond_other_d0.0010.0164084
X-RAY DIFFRACTIONr_angle_refined_deg1.7611.8415873
X-RAY DIFFRACTIONr_angle_other_deg0.5981.7499406
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4535523
X-RAY DIFFRACTIONr_dihedral_angle_2_deg13.8587.14342
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.05510710
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0840.2637
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.025101
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021029
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.6532.852122
X-RAY DIFFRACTIONr_mcbond_other2.6532.8492121
X-RAY DIFFRACTIONr_mcangle_it3.725.0942635
X-RAY DIFFRACTIONr_mcangle_other3.725.0942636
X-RAY DIFFRACTIONr_scbond_it3.3733.1652219
X-RAY DIFFRACTIONr_scbond_other3.3723.1642220
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.0425.6713239
X-RAY DIFFRACTIONr_long_range_B_refined7.06934.7518243
X-RAY DIFFRACTIONr_long_range_B_other7.05334.5418131
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.8→1.847 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.313 169 -
Rwork0.263 3371 -
obs--99.33 %

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