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- PDB-7apg: Crystal structure of JAK3 in complex with FM587 (compound 9a) -

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Basic information

Entry
Database: PDB / ID: 7apg
TitleCrystal structure of JAK3 in complex with FM587 (compound 9a)
ComponentsTyrosine-protein kinase JAK3
KeywordsTRANSFERASE / kinase / JAK3 / inhibitor / covalent inhibitor / Structural Genomics / Structural Genomics Consortium / SGC
Function / homology
Function and homology information


negative regulation of dendritic cell cytokine production / negative regulation of FasL 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 / negative regulation of T cell activation / Interleukin-9 signaling / Interleukin-21 signaling ...negative regulation of dendritic cell cytokine production / negative regulation of FasL 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 / negative regulation of T cell activation / Interleukin-9 signaling / Interleukin-21 signaling / interleukin-9-mediated signaling pathway / interleukin-4-mediated signaling pathway / interleukin-2-mediated signaling pathway / regulation of T cell apoptotic process / negative regulation of interleukin-12 production / interleukin-15-mediated signaling pathway / tyrosine phosphorylation of STAT protein / negative regulation of thymocyte apoptotic process / Interleukin-15 signaling / Interleukin-2 signaling / regulation of receptor signaling pathway via JAK-STAT / growth hormone receptor binding / Signaling by ALK / extrinsic component of plasma membrane / negative regulation of interleukin-10 production / Interleukin-20 family signaling / enzyme-linked receptor protein signaling pathway / T cell homeostasis / cell surface receptor signaling pathway via JAK-STAT / growth hormone receptor signaling pathway via JAK-STAT / Interleukin receptor SHC signaling / extrinsic component of cytoplasmic side of plasma membrane / Interleukin-7 signaling / B cell differentiation / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / cytokine-mediated signaling pathway / peptidyl-tyrosine phosphorylation / RAF/MAP kinase cascade / protein phosphatase binding / protein tyrosine kinase activity / Interleukin-4 and Interleukin-13 signaling / regulation of apoptotic process / Potential therapeutics for SARS / adaptive immune response / cell differentiation / cytoskeleton / endosome / intracellular signal transduction / protein phosphorylation / 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 / FERM domain / FERM domain profile. ...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 / 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 / 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
1-phenylurea / Chem-RQT / Tyrosine-protein kinase JAK3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsChaikuad, A. / Forster, M. / Gehringer, M. / Laufer, S. / Knapp, S. / Structural Genomics Consortium (SGC)
CitationJournal: Int J Mol Sci / Year: 2020
Title: Discovery of a Novel Class of Covalent Dual Inhibitors Targeting the Protein Kinases BMX and BTK.
Authors: Forster, M. / Liang, X.J. / Schroder, M. / Gerstenecker, S. / Chaikuad, A. / Knapp, S. / Laufer, S. / Gehringer, M.
History
DepositionOct 16, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 2, 2020Provider: repository / Type: Initial release
Revision 1.1Jan 13, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jan 31, 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 / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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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)136,39230
Polymers133,6694
Non-polymers2,72326
Water6,071337
1
A: Tyrosine-protein kinase JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,0056
Polymers33,4171
Non-polymers5885
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,0677
Polymers33,4171
Non-polymers6506
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Tyrosine-protein kinase JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,1298
Polymers33,4171
Non-polymers7127
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Tyrosine-protein kinase JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,1919
Polymers33,4171
Non-polymers7748
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)57.469, 112.883, 102.897
Angle α, β, γ (deg.)90.000, 97.210, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22C
13A
23D
14B
24C
15B
25D
16C
26D

NCS domain segments:

Component-ID: 0 / Refine code: 0

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11PROPROSERSERAA814 - 11025 - 293
21PROPROSERSERBB814 - 11025 - 293
12ASPASPARGARGAA813 - 11034 - 294
22ASPASPARGARGCC813 - 11034 - 294
13THRTHRSERSERAA815 - 11026 - 293
23THRTHRSERSERDD815 - 11026 - 293
14PROPROARGARGBB814 - 11035 - 294
24PROPROARGARGCC814 - 11035 - 294
15THRTHRSERSERBB815 - 11026 - 293
25THRTHRSERSERDD815 - 11026 - 293
16THRTHRARGARGCC815 - 11036 - 294
26THRTHRARGARGDD815 - 11036 - 294

NCS ensembles :
ID
1
2
3
4
5
6

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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.: 4
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-RQT / ~{N}-[3-(1~{H}-pyrrolo[2,3-b]pyridin-3-yl)phenyl]propanamide


Mass: 265.310 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C16H15N3O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-PHU / 1-phenylurea / Phenylurea


Mass: 136.151 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C7H8N2O
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 18 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 337 / 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: 2.48 Å3/Da / Density % sol: 50.35 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop / pH: 5.5
Details: 25% PEG 3350, 0.1-0.2 M MgCl2 and 0.1 M MES, pH 5.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.99986 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Apr 18, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99986 Å / Relative weight: 1
ReflectionResolution: 2.4→49.39 Å / Num. obs: 50511 / % possible obs: 99.2 % / Redundancy: 4.6 % / CC1/2: 0.994 / Rmerge(I) obs: 0.126 / Rpim(I) all: 0.075 / Rrim(I) all: 0.162 / Net I/σ(I): 6.6
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
2.4-2.534.30.6291.872450.7910.3980.83798.1
7.59-49.394.70.05616620.9950.0290.06399.7

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Processing

Software
NameVersionClassification
Aimless0.7.1data scaling
REFMAC5.8.0222refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5lwm

5lwm


Resolution: 2.4→49.39 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.915 / SU B: 18.548 / SU ML: 0.214 / SU R Cruickshank DPI: 0.5067 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.507 / ESU R Free: 0.279 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2557 2497 4.9 %RANDOM
Rwork0.2122 ---
obs0.2143 47992 99.11 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 125.58 Å2 / Biso mean: 39.666 Å2 / Biso min: 11.09 Å2
Baniso -1Baniso -2Baniso -3
1--0.86 Å2-0 Å20.33 Å2
2---0.09 Å2-0 Å2
3---0.84 Å2
Refinement stepCycle: final / Resolution: 2.4→49.39 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8919 0 212 337 9468
Biso mean--34.04 33.55 -
Num. residues----1123
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0149379
X-RAY DIFFRACTIONr_bond_other_d0.0010.0178365
X-RAY DIFFRACTIONr_angle_refined_deg1.0821.64612644
X-RAY DIFFRACTIONr_angle_other_deg0.8561.65519599
X-RAY DIFFRACTIONr_dihedral_angle_1_deg19.5245.4111168
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.72720.539501
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.663151528
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.0921584
X-RAY DIFFRACTIONr_chiral_restr0.060.21114
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0212222
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021794
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.06 Å / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumber
11A9014
12B9014
21A9068
22C9068
31A9023
32D9023
41B9040
42C9040
51B8968
52D8968
61C8976
62D8976
LS refinement shellResolution: 2.4→2.462 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.334 162 -
Rwork0.299 3484 -
all-3646 -
obs--98.81 %
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)
12.9462-0.59540.84696.5255-0.50836.3344-0.00080.0514-0.4641-0.43940.00240.33360.3182-0.03-0.00160.1049-0.0296-0.01240.0467-0.0610.2759-48.9958-19.4217-55.5215
22.1936-0.21810.91332.2962-0.20170.4581-0.0175-0.0194-0.10730.02780.0453-0.0081-0.0338-0.0036-0.02780.20610.0174-0.02290.00470.00290.2578-40.9374-5.8165-47.8737
32.9012-0.88470.67712.5864-0.77131.4809-0.2572-0.60570.33090.54330.1693-0.3698-0.1578-0.21450.08790.30540.0335-0.12480.1407-0.09190.2075-33.88262.007-31.7961
44.591-0.192-1.97143.9262-1.39833.93540.1551-0.12690.25420.45140.1560.4075-0.4534-0.1798-0.31120.26280.03210.01840.02430.03240.2797-25.1545-2.95014.1049
53.1229-0.619-1.00021.837-0.50590.61010.0550.10330.1139-0.11910.01490.05660.0263-0.0441-0.06980.2157-0.0232-0.06180.02750.01330.233-18.9078-18.7104-3.8459
61.9698-0.70390.29931.7004-0.41090.83860.20420.2505-0.0291-0.4957-0.23110.00060.1111-0.00460.02690.33170.0819-0.07380.0793-0.0210.1697-11.0194-26.9239-18.2159
71.1438-0.5469-0.91692.8779-2.24225.39230.0273-0.10470.09390.10070.1780.1826-0.1572-0.3143-0.20530.1560.0056-0.05420.07570.00230.2297-19.219630.6322-44.3319
82.8281-0.5053-0.93732.3461-0.51610.51940.0535-0.003-0.0116-0.22670.00440.14790.04310.0002-0.05780.2461-0.0163-0.0890.00120.00290.2704-12.253616.5989-53.9274
91.2133-0.61420.38542.5287-0.15450.83930.24710.045-0.1524-0.8491-0.31410.016-0.009-0.04520.0670.53620.1171-0.07330.0579-0.05530.2137-5.80229.1371-70.3237
101.13660.1060.63491.46240.46680.7305-0.017-0.0316-0.05240.13440.0432-0.04940.0164-0.0351-0.02620.2006-0.0261-0.03150.0116-0.00310.2507-8.603313.1221-2.1706
112.24481.14140.71991.98840.6431.7493-0.09590.24850.0628-0.2140.08980.03660.0260.11970.00610.2117-0.0185-0.03870.061-0.00210.2172-12.012321.7438-20.6135
122.3308-0.1657-0.85931.50350.54582.4448-0.09560.2930.2081-0.08920.01580.2467-0.0989-0.20590.07980.1936-0.0127-0.07850.06340.0130.2246-23.482326.8866-17.438
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A813 - 846
2X-RAY DIFFRACTION2A847 - 983
3X-RAY DIFFRACTION3A984 - 1103
4X-RAY DIFFRACTION4B814 - 854
5X-RAY DIFFRACTION5B855 - 990
6X-RAY DIFFRACTION6B991 - 1103
7X-RAY DIFFRACTION7C810 - 852
8X-RAY DIFFRACTION8C853 - 984
9X-RAY DIFFRACTION9C985 - 1103
10X-RAY DIFFRACTION10D815 - 984
11X-RAY DIFFRACTION11D985 - 1051
12X-RAY DIFFRACTION12D1052 - 1103

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