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- PDB-6glb: Crystal structure of JAK3 in complex with Compound 20 (FM484) -

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Basic information

Entry
Database: PDB / ID: 6glb
TitleCrystal structure of JAK3 in complex with Compound 20 (FM484)
ComponentsTyrosine-protein kinase JAK3
KeywordsTRANSFERASE / KINASE / JAK3 / COVALENT INHIBITOR / REVERSIBLE COVALENT INHIBITOR / INDUCED POCKET / ARGININE POCKET / 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 / extrinsic component of plasma membrane / Signaling by ALK / 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 / regulation of apoptotic process / protein phosphatase binding / protein tyrosine kinase activity / Interleukin-4 and Interleukin-13 signaling / adaptive immune response / Potential therapeutics for SARS / 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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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-F48 / 1-phenylurea / Tyrosine-protein kinase JAK3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsChaikuad, A. / Forster, M. / von Delft, F. / Edwards, A.M. / Arrowsmith, C.H. / Bountra, C. / Laufer, S.A. / Knapp, S. / Structural Genomics Consortium (SGC)
CitationJournal: J. Med. Chem. / Year: 2018
Title: Development, Optimization, and Structure-Activity Relationships of Covalent-Reversible JAK3 Inhibitors Based on a Tricyclic Imidazo[5,4- d]pyrrolo[2,3- b]pyridine Scaffold.
Authors: Forster, M. / Chaikuad, A. / Dimitrov, T. / Doring, E. / Holstein, J. / Berger, B.T. / Gehringer, M. / Ghoreschi, K. / Muller, S. / Knapp, S. / Laufer, S.A.
History
DepositionMay 23, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 27, 2018Provider: repository / Type: Initial release
Revision 1.1Jul 11, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Jan 17, 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

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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)68,13611
Polymers66,8352
Non-polymers1,3019
Water4,360242
1
A: Tyrosine-protein kinase JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,0996
Polymers33,4171
Non-polymers6825
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,0375
Polymers33,4171
Non-polymers6204
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)41.849, 50.309, 61.588
Angle α, β, γ (deg.)91.74, 90.28, 92.76
Int Tables number1
Space group name H-MP1
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: 0 / Ens-ID: 1 / Beg auth comp-ID: ASP / Beg label comp-ID: ASP / End auth comp-ID: ARG / End label comp-ID: ARG / Refine code: 0 / Auth seq-ID: 813 - 1103 / Label seq-ID: 4 - 294

Dom-IDAuth asym-IDLabel asym-ID
1AA
2BB

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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-F48 / 3-[5-(3-cyclohexyl-3,5,8,10-tetrazatricyclo[7.3.0.0^{2,6}]dodeca-1(9),2(6),4,7,11-pentaen-4-yl)furan-2-yl]propanenitrile


Mass: 359.424 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H21N5O
#3: Chemical ChemComp-PHU / 1-phenylurea / Phenylurea


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


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


Mass: 18.015 Da / Num. of mol.: 242 / Source method: isolated from a natural source / Formula: H2O

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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: 1.94 Å3/Da / Density % sol: 36.5 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop
Details: 24-30% PEG 3350, 0.1 M MES, pH 5.5-6.0 and 0.1-0.2 M MgCl2
PH range: 5.5-6.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97625 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: May 16, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 2→61.558 Å / Num. all: 30795 / Num. obs: 30795 / % possible obs: 90.9 % / Redundancy: 2.4 % / Rpim(I) all: 0.091 / Rrim(I) all: 0.154 / Rsym value: 0.123 / Net I/av σ(I): 4.8 / Net I/σ(I): 5.5 / Num. measured all: 74635
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique obsRpim(I) allRrim(I) allRsym valueNet I/σ(I) obs% possible all
2-2.112.40.3521056243850.2570.4360.352.489.3
2.11-2.242.30.2642.6946341980.2050.3370.264389.8
2.24-2.392.30.2153.3929239720.160.2690.2153.789.8
2.39-2.582.40.1753.9904837500.1310.220.1754.591.3
2.58-2.832.40.154.5831234400.1130.1890.155.491.7
2.83-3.162.60.1185.8805431190.0840.1460.1186.891.5
3.16-3.652.60.0917717927810.0650.1120.0918.692.5
3.65-4.472.50.0827.7576223480.0610.1030.0829.992.6
4.47-6.322.40.0996.2439118070.0720.1230.0999.691.8
6.32-41.7992.60.0727.725729950.0530.090.07210.192.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0135refinement
XDSdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5lwm

5lwm


Resolution: 2→61.56 Å / Cor.coef. Fo:Fc: 0.898 / Cor.coef. Fo:Fc free: 0.851 / SU B: 13.928 / SU ML: 0.198 / Cross valid method: THROUGHOUT / ESU R: 0.351 / ESU R Free: 0.25 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.29026 1470 4.8 %RANDOM
Rwork0.2331 ---
obs0.23578 29323 90.93 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 23.105 Å2
Baniso -1Baniso -2Baniso -3
1--2.32 Å21.35 Å2-0.02 Å2
2--1.6 Å2-0.09 Å2
3---0.59 Å2
Refinement stepCycle: 1 / Resolution: 2→61.56 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4580 0 94 242 4916
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0194805
X-RAY DIFFRACTIONr_bond_other_d0.0040.024565
X-RAY DIFFRACTIONr_angle_refined_deg1.5631.9766490
X-RAY DIFFRACTIONr_angle_other_deg1.073310493
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.785576
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.43722.455220
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.3115808
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.4241548
X-RAY DIFFRACTIONr_chiral_restr0.0880.2680
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0215676
X-RAY DIFFRACTIONr_gen_planes_other0.0040.021152
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_it0.8631.4942308
X-RAY DIFFRACTIONr_mcbond_other0.8641.4942303
X-RAY DIFFRACTIONr_mcangle_it1.5492.2342878
X-RAY DIFFRACTIONr_mcangle_other1.5492.2342877
X-RAY DIFFRACTIONr_scbond_it0.7081.5642497
X-RAY DIFFRACTIONr_scbond_other0.7081.5642497
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other1.2192.3053611
X-RAY DIFFRACTIONr_long_range_B_refined4.16611.765426
X-RAY DIFFRACTIONr_long_range_B_other4.16611.7635427
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Ens-ID: 1 / Number: 36118 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.03 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 2→2.052 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.361 119 -
Rwork0.297 2089 -
obs--89.5 %
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)
10.816-0.0331-0.18690.7298-0.05430.20160.00650.04070.07510.0258-0.0196-0.0382-0.00710.00320.0130.0395-0.069-0.00080.12480.00550.013234.008954.55977.7297
21.14970.01050.16250.93160.0241.4364-0.0351-0.0134-0.1228-0.00650.02040.08810.0913-0.02740.01470.0498-0.06690.01770.1025-0.01660.02622.12935.19095.0279
30.83060.05160.38630.90940.12580.21380.05480.0517-0.05750.0313-0.03740.00360.02230.0115-0.01740.0476-0.06290.00670.1128-0.02390.00864.013445.0894-23.4576
41.44210.2285-0.16990.2425-0.08871.08720.0035-0.02810.10110.00570.0048-0.0636-0.14030.0694-0.00830.054-0.05870.00450.0751-0.01240.053715.925264.5786-24.7815
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A813 - 990
2X-RAY DIFFRACTION2A991 - 1103
3X-RAY DIFFRACTION3B813 - 990
4X-RAY DIFFRACTION4B991 - 1103

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