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- PDB-6hzv: HUMAN JAK3 IN COMPLEX WITH LASW959 PROTEIN IN COMPLEX WITH LIGAND -

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Basic information

Entry
Database: PDB / ID: 6hzv
TitleHUMAN JAK3 IN COMPLEX WITH LASW959 PROTEIN IN COMPLEX WITH LIGAND
ComponentsTyrosine-protein kinase JAK3
KeywordsPROTEIN BINDING / PROTEIN KINASE / JANUS KINASE / JAK3 / Proteros Biostructures GMBH
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 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 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 / growth hormone receptor binding / negative regulation of thymocyte apoptotic process / Interleukin-15 signaling / regulation of receptor signaling pathway via JAK-STAT / Interleukin-2 signaling / extrinsic component of cytoplasmic side of plasma membrane / extrinsic component of plasma membrane / Interleukin-20 family signaling / Signaling by ALK / negative regulation of interleukin-10 production / enzyme-linked receptor protein signaling pathway / T cell homeostasis / growth hormone receptor signaling pathway via JAK-STAT / cell surface receptor signaling pathway via JAK-STAT / Interleukin receptor SHC signaling / Interleukin-7 signaling / B cell differentiation / non-membrane spanning protein tyrosine kinase activity / non-specific protein-tyrosine kinase / cytokine-mediated signaling pathway / cytoplasmic side of plasma membrane / 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 / : / SH2 domain / Jak1 pleckstrin homology-like domain / FERM F2 acyl-CoA binding protein-like domain / FERM F1 ubiquitin-like 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 / : / SH2 domain / Jak1 pleckstrin homology-like domain / FERM F2 acyl-CoA binding protein-like domain / FERM F1 ubiquitin-like 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. / 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
Chem-GYW / Tyrosine-protein kinase JAK3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.46 Å
AuthorsLozoya, E. / Segarra, V. / Bach, J. / Jestel, A. / Lammens, A. / Blaesse, M.
CitationJournal: J.Med.Chem. / Year: 2019
Title: Identification of 2-Imidazopyridine and 2-Aminopyridone Purinones as Potent Pan-Janus Kinase (JAK) Inhibitors for the Inhaled Treatment of Respiratory Diseases.
Authors: Bach, J. / Eastwood, P. / Gonzalez, J. / Gomez, E. / Alonso, J.A. / Fonquerna, S. / Lozoya, E. / Orellana, A. / Maldonado, M. / Calaf, E. / Alberti, J. / Perez, J. / Andres, A. / Prats, N. / ...Authors: Bach, J. / Eastwood, P. / Gonzalez, J. / Gomez, E. / Alonso, J.A. / Fonquerna, S. / Lozoya, E. / Orellana, A. / Maldonado, M. / Calaf, E. / Alberti, J. / Perez, J. / Andres, A. / Prats, N. / Carreno, C. / Calama, E. / De Alba, J. / Calbet, M. / Miralpeix, M. / Ramis, I.
History
DepositionOct 24, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 23, 2019Provider: repository / Type: Initial release
Revision 1.1Oct 30, 2019Group: Data collection / Structure summary / Category: audit_author / Item: _audit_author.name
Revision 1.2Nov 6, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Jan 24, 2024Group: 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
Revision 1.4Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)132,3838
Polymers130,7614
Non-polymers1,6224
Water1,928107
1
A: Tyrosine-protein kinase JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,0962
Polymers32,6901
Non-polymers4051
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Tyrosine-protein kinase JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,0962
Polymers32,6901
Non-polymers4051
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Tyrosine-protein kinase JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,0962
Polymers32,6901
Non-polymers4051
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: Tyrosine-protein kinase JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,0962
Polymers32,6901
Non-polymers4051
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)57.072, 112.814, 104.466
Angle α, β, γ (deg.)90.00, 98.30, 90.00
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
31C
41D
12A
22B
32C
42D

NCS domain segments:
Dom-IDComponent-IDEns-IDRefine codeAuth asym-IDAuth seq-ID
1114A1 - 907
2114B1 - 907
3114C1 - 907
4114D1 - 907
1124A908 - 2000
2124B908 - 2000
3124C908 - 2000
4124D908 - 2000

NCS ensembles :
ID
1
2

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Components

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


Mass: 32690.301 Da / Num. of mol.: 4 / Fragment: KINASE DOMAIN / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
References: UniProt: P52333, non-specific protein-tyrosine kinase
#2: Chemical
ChemComp-GYW / 3-[7-(2-hydroxyethyl)-9-(oxan-4-yl)-8-oxidanylidene-purin-2-yl]imidazo[1,2-a]pyridine-6-carbonitrile


Mass: 405.410 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C20H19N7O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 107 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.52 Å3/Da / Density % sol: 51.3 %
Crystal growTemperature: 277 K / Method: vapor diffusion / Details: 30% PEG3350, 0.1M BIS-TRIS, 0.2M MgCl, pH 6.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SRS / Beamline: PX10.1 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Dec 4, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.46→43.23 Å / Num. obs: 47359 / % possible obs: 99.5 % / Observed criterion σ(I): 0 / Redundancy: 4.3 % / Rmerge(I) obs: 0.118 / Net I/σ(I): 11.1
Reflection shellResolution: 2.46→2.68 Å / Redundancy: 4.3 % / Rmerge(I) obs: 0.767 / % possible all: 98.8

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
REFMAC5.2.0005refinement
REFMAC5.2.0005phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1YVJ

1yvj


Resolution: 2.46→43.23 Å / Cor.coef. Fo:Fc: 0.926 / Cor.coef. Fo:Fc free: 0.87 / SU B: 22.375 / SU ML: 0.243 / Cross valid method: THROUGHOUT / ESU R: 0.489 / ESU R Free: 0.297 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.27533 1000 2.1 %RANDOM
Rwork0.22278 ---
obs0.2239 46359 100 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 37.51 Å2
Baniso -1Baniso -2Baniso -3
1--1.17 Å20 Å2-0.04 Å2
2---2.15 Å20 Å2
3---3.31 Å2
Refinement stepCycle: LAST / Resolution: 2.46→43.23 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8543 0 120 107 8770
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0228888
X-RAY DIFFRACTIONr_bond_other_d0.0010.028116
X-RAY DIFFRACTIONr_angle_refined_deg0.927212024
X-RAY DIFFRACTIONr_angle_other_deg0.7212.99818835
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.32551043
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.18822.802414
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.985151520
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.7631583
X-RAY DIFFRACTIONr_chiral_restr0.0530.21277
X-RAY DIFFRACTIONr_gen_planes_refined0.0020.029647
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021875
X-RAY DIFFRACTIONr_nbd_refined0.1890.21694
X-RAY DIFFRACTIONr_nbd_other0.1630.27925
X-RAY DIFFRACTIONr_nbtor_refined0.1740.24259
X-RAY DIFFRACTIONr_nbtor_other0.080.24798
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1090.2197
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1310.222
X-RAY DIFFRACTIONr_symmetry_vdw_other0.1760.2144
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1120.25
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.99526819
X-RAY DIFFRACTIONr_mcbond_other0.19122122
X-RAY DIFFRACTIONr_mcangle_it1.19938488
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.80744325
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it2.65963535
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION

Ens-IDDom-IDAuth asym-IDNumberTypeRms dev position (Å)Weight position
11A1327medium positional0.330.5
12B1327medium positional0.360.5
13C1327medium positional0.390.5
14D1327medium positional0.330.5
21A2654medium positional0.280.5
22B2654medium positional0.310.5
23C2654medium positional0.260.5
24D2654medium positional0.220.5
11A1327medium thermal0.212
12B1327medium thermal0.222
13C1327medium thermal0.212
14D1327medium thermal0.22
21A2654medium thermal0.222
22B2654medium thermal0.22
23C2654medium thermal0.212
24D2654medium thermal0.22
LS refinement shellResolution: 2.461→2.524 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.363 73 -
Rwork0.334 3380 -
obs--100 %
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)
12.9977-0.91770.958.4452-2.2631.14390.0331-0.006-0.3579-0.19080.13571.0450.0556-0.2416-0.1687-0.07460.0077-0.06840.0091-0.0410.042.38527.287-5.057
21.7771-0.14680.77732.86850.64343.4246-0.0148-0.2996-0.02120.3723-0.03840.21160.0043-0.2590.0531-0.102-0.03920.0255-0.0065-0.0069-0.082315.3739.78612.611
32.3398-1.158-0.86276.71370.90971.28210.0009-0.00880.2077-0.2570.0324-0.7774-0.0150.2639-0.0333-0.04980.00740.0313-0.00970.0153-0.074126.2798.314-4.762
41.6713-0.209-0.20843.2187-1.02323.4673-0.009-0.40.00160.4814-0.0285-0.0246-0.05820.16840.0375-0.0622-0.0566-0.01910.0354-0.0063-0.078513.01-3.65212.768
52.21510.2038-0.52555.4654-1.48121.7249-0.00620.05110.26470.18610.14880.58-0.0758-0.3275-0.1427-0.06240.00650.0305-0.02180.0056-0.093324.047-8.45952.295
61.646-0.2383-0.13.66881.10352.9004-0.06040.2377-0.0888-0.46430.099-0.044-0.0093-0.0159-0.0387-0.10480.0099-0.0217-0.0369-0.0134-0.092136.302-25.06137.757
72.48480.06710.36544.452-1.48552.2334-0.08590.0016-0.2767-0.09290.19650.56730.0692-0.2995-0.1107-0.0411-0.0041-0.0405-0.04490.00950.0228-4.488-47.2151.191
82.82830.44050.72695.1655-0.09163.03450.0721-0.41250.02830.88410.01890.4329-0.1716-0.096-0.09110.0149-0.04310.0651-0.0275-0.024-0.07918.128-30.69965.044
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A815 - 904
2X-RAY DIFFRACTION2A905 - 1098
3X-RAY DIFFRACTION3B815 - 904
4X-RAY DIFFRACTION4B905 - 1098
5X-RAY DIFFRACTION5C815 - 904
6X-RAY DIFFRACTION6C905 - 1098
7X-RAY DIFFRACTION7D815 - 904
8X-RAY DIFFRACTION8D905 - 1098

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