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- PDB-6gl9: Crystal structure of JAK3 in complex with Compound 10 (FM475) -

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Basic information

Entry
Database: PDB / ID: 6gl9
TitleCrystal structure of JAK3 in complex with Compound 10 (FM475)
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 / : / 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-F3W / 1-phenylurea / Tyrosine-protein kinase JAK3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 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

Downloads & links

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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)68,83321
Polymers66,8352
Non-polymers1,99819
Water5,783321
1
A: Tyrosine-protein kinase JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,44711
Polymers33,4171
Non-polymers1,03010
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,38510
Polymers33,4171
Non-polymers9689
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)42.020, 50.424, 61.588
Angle α, β, γ (deg.)91.93, 90.03, 92.80
Int Tables number1
Space group name H-MP1
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: _ / Ens-ID: 1 / Beg auth comp-ID: ASP / Beg label comp-ID: ASP / End auth comp-ID: SER / End label comp-ID: SER / Refine code: _ / Auth seq-ID: 813 - 1102 / Label seq-ID: 4 - 293

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

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Components

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Protein , 1 types, 2 molecules AB

#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

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Non-polymers , 5 types, 340 molecules

#2: Chemical ChemComp-F3W / (~{E})-3-[3-(3-cyclohexyl-3,5,8,10-tetrazatricyclo[7.3.0.0^{2,6}]dodeca-1(9),2(6),4,7,11-pentaen-4-yl)phenyl]prop-2-enenitrile


Mass: 367.446 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H21N5
#3: Chemical ChemComp-PHU / 1-phenylurea / Phenylurea


Mass: 136.151 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C7H8N2O
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 13 / Source method: obtained synthetically / Formula: C2H6O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 321 / 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: 1.95 Å3/Da / Density % sol: 36.89 %
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: 1.7→19.81 Å / Num. obs: 54150 / % possible obs: 97.5 % / Redundancy: 3.5 % / Rmerge(I) obs: 0.086 / Net I/σ(I): 8.3
Reflection shellResolution: 1.7→1.79 Å / Redundancy: 3.6 % / Rmerge(I) obs: 0.614 / Mean I/σ(I) obs: 2 / Num. unique obs: 7825 / % possible all: 96

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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: 1.7→19.81 Å / Cor.coef. Fo:Fc: 0.946 / Cor.coef. Fo:Fc free: 0.924 / SU B: 6.503 / SU ML: 0.107 / Cross valid method: THROUGHOUT / ESU R: 0.148 / ESU R Free: 0.135 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2438 2503 4.6 %RANDOM
Rwork0.20688 ---
obs0.20863 51642 97.45 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 24.922 Å2
Baniso -1Baniso -2Baniso -3
1--1.23 Å20.17 Å2-0.09 Å2
2--1.42 Å20.4 Å2
3----0.24 Å2
Refinement stepCycle: 1 / Resolution: 1.7→19.81 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4634 0 140 321 5095
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0194982
X-RAY DIFFRACTIONr_bond_other_d0.0050.024763
X-RAY DIFFRACTIONr_angle_refined_deg1.6581.9836731
X-RAY DIFFRACTIONr_angle_other_deg1.197310970
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.175609
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.56122.719228
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.39915844
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.9271548
X-RAY DIFFRACTIONr_chiral_restr0.1010.2703
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0215941
X-RAY DIFFRACTIONr_gen_planes_other0.0040.021187
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_it1.081.42368
X-RAY DIFFRACTIONr_mcbond_other1.0811.3992363
X-RAY DIFFRACTIONr_mcangle_it1.9192.0932965
X-RAY DIFFRACTIONr_mcangle_other1.9192.0932964
X-RAY DIFFRACTIONr_scbond_it1.1271.5562614
X-RAY DIFFRACTIONr_scbond_other1.1271.5562614
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other1.8472.2563755
X-RAY DIFFRACTIONr_long_range_B_refined5.3411.765708
X-RAY DIFFRACTIONr_long_range_B_other5.3411.7665709
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Ens-ID: 1 / Number: 35248 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.07 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 1.7→1.744 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.334 183 -
Rwork0.276 3782 -
obs--95.87 %
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)
11.42770.2861-0.38371.4892-0.02270.64280.03650.10090.15740.0055-0.0507-0.0435-0.0774-0.02060.01410.01930.0074-0.02240.04890.02180.079336.64432.255770.5167
22.7561-0.08780.3861.50840.46421.99210.01090.0842-0.1365-0.0505-0.00990.03760.153-0.0467-0.0010.0266-0.0154-0.00130.017-0.00890.100724.4349-16.730167.3005
31.2630.35570.43231.31770.05080.86990.06080.0829-0.15870.0031-0.04370.03280.10820.0174-0.01710.03140.01550.00080.024-0.01640.0836.0251-7.565539.3113
42.29170.1163-0.14431.3393-0.6151.96160.01580.00660.0935-0.0353-0.0186-0.0473-0.16170.03440.00290.0344-0.0074-0.0120.0049-0.00660.093818.273911.413637.4834
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A812 - 984
2X-RAY DIFFRACTION2A985 - 1103
3X-RAY DIFFRACTION3B813 - 984
4X-RAY DIFFRACTION4B985 - 1103

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