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- PDB-3lxp: Structural and Thermodynamic Characterization of the TYK2 and JAK... -

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Basic information

Entry
Database: PDB / ID: 3lxp
TitleStructural and Thermodynamic Characterization of the TYK2 and JAK3 Kinase Domains in Complex with CP-690550 and CMP-6
ComponentsNon-receptor tyrosine-protein kinase TYK2
KeywordsTRANSFERASE / TYK2 / JAK3 / inflammation / cancer / PAN Inhibitor / ATP-binding / Kinase / Nucleotide-binding / Phosphoprotein / SH2 domain / Tyrosine-protein kinase
Function / homology
Function and homology information


type III interferon-mediated signaling pathway / interleukin-10-mediated signaling pathway / interleukin-12 receptor complex / interleukin-23 receptor complex / interleukin-23-mediated signaling pathway / Interleukin-23 signaling / positive regulation of T-helper 17 type immune response / interleukin-12-mediated signaling pathway / positive regulation of NK T cell proliferation / Interleukin-12 signaling ...type III interferon-mediated signaling pathway / interleukin-10-mediated signaling pathway / interleukin-12 receptor complex / interleukin-23 receptor complex / interleukin-23-mediated signaling pathway / Interleukin-23 signaling / positive regulation of T-helper 17 type immune response / interleukin-12-mediated signaling pathway / positive regulation of NK T cell proliferation / Interleukin-12 signaling / IL-6-type cytokine receptor ligand interactions / Interleukin-27 signaling / Interleukin-35 Signalling / growth hormone receptor binding / extrinsic component of cytoplasmic side of plasma membrane / Other interleukin signaling / extrinsic component of plasma membrane / Interleukin-20 family signaling / Interleukin-6 signaling / type I interferon-mediated signaling pathway / MAPK3 (ERK1) activation / MAPK1 (ERK2) activation / Interleukin-10 signaling / positive regulation of interleukin-17 production / positive regulation of natural killer cell proliferation / Regulation of IFNA/IFNB signaling / growth hormone receptor signaling pathway via JAK-STAT / cell surface receptor signaling pathway via JAK-STAT / type II interferon-mediated signaling pathway / Signaling by CSF3 (G-CSF) / positive regulation of T cell proliferation / non-membrane spanning protein tyrosine kinase activity / positive regulation of receptor signaling pathway via JAK-STAT / non-specific protein-tyrosine kinase / Inactivation of CSF3 (G-CSF) signaling / cellular response to virus / Evasion by RSV of host interferon responses / positive regulation of protein localization to nucleus / cytoplasmic side of plasma membrane / positive regulation of type II interferon production / cytokine-mediated signaling pathway / Interferon alpha/beta signaling / Signaling by ALK fusions and activated point mutants / protein tyrosine kinase activity / Interleukin-4 and Interleukin-13 signaling / Potential therapeutics for SARS / cell differentiation / cytoskeleton / cell population proliferation / protein phosphorylation / receptor complex / intracellular signal transduction / immune response / SARS-CoV-2 activates/modulates innate and adaptive immune responses / extracellular exosome / ATP binding / nucleus / plasma membrane / cytoplasm / cytosol
Similarity search - Function
Tyrosine-protein kinase, non-receptor, TYK2, N-terminal / 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, TYK2, N-terminal / 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 superfamily, second 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 / 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-IZA / Non-receptor tyrosine-protein kinase TYK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.65 Å
AuthorsChrencik, J.E. / Benson, T.E.
CitationJournal: J.Mol.Biol. / Year: 2010
Title: Structural and thermodynamic characterization of the TYK2 and JAK3 kinase domains in complex with CP-690550 and CMP-6.
Authors: Chrencik, J.E. / Patny, A. / Leung, I.K. / Korniski, B. / Emmons, T.L. / Hall, T. / Weinberg, R.A. / Gormley, J.A. / Williams, J.M. / Day, J.E. / Hirsch, J.L. / Kiefer, J.R. / Leone, J.W. / ...Authors: Chrencik, J.E. / Patny, A. / Leung, I.K. / Korniski, B. / Emmons, T.L. / Hall, T. / Weinberg, R.A. / Gormley, J.A. / Williams, J.M. / Day, J.E. / Hirsch, J.L. / Kiefer, J.R. / Leone, J.W. / Fischer, H.D. / Sommers, C.D. / Huang, H.C. / Jacobsen, E.J. / Tenbrink, R.E. / Tomasselli, A.G. / Benson, T.E.
History
DepositionFeb 25, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 2, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 13, 2021Group: Database references / Derived calculations
Category: database_2 / struct_conn ...database_2 / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3Sep 6, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.4Nov 22, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2
Revision 1.5Oct 9, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Non-receptor tyrosine-protein kinase TYK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,8442
Polymers36,5351
Non-polymers3091
Water3,135174
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)38.325, 75.978, 97.415
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Non-receptor tyrosine-protein kinase TYK2


Mass: 36534.570 Da / Num. of mol.: 1 / Fragment: Kinase Domain / Mutation: C936A, Q969A, E971A, K972A, C1142A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TYK2 / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): Sf21
References: UniProt: P29597, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-IZA / 2-TERT-BUTYL-9-FLUORO-3,6-DIHYDRO-7H-BENZ[H]-IMIDAZ[4,5-F]ISOQUINOLINE-7-ONE / 2-(1,1-DIMETHYLETHYL)9-FLUORO-3,6-DIHYDRO-7H-BENZ[H]-IMIDAZ[4,5-F]ISOQUINOLIN-7-ONE


Mass: 309.338 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H16FN3O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 174 / 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: 1.94 Å3/Da / Density % sol: 36.63 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8
Details: 10% Ethanol, 0.1 M Tris, and 0.3 M magnesium chloride, pH 8.0, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 1.5418 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Jul 7, 2009 / Details: mirror
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.65→35.4 Å / Num. all: 33373 / Num. obs: 33373 / % possible obs: 99.7 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 5.5 % / Rsym value: 0.08 / Net I/σ(I): 23.4
Reflection shellResolution: 1.65→1.69 Å / Redundancy: 4.6 % / Mean I/σ(I) obs: 1.7 / Rsym value: 0.54 / % possible all: 98.2

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Processing

Software
NameVersionClassification
HKL-2000data collection
AMoREphasing
REFMAC5.2.0019refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 1YVJ

1yvj


Resolution: 1.65→35.4 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.934 / SU B: 1.912 / SU ML: 0.067 / Cross valid method: THROUGHOUT / ESU R: 0.104 / ESU R Free: 0.104 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22874 1761 5 %RANDOM
Rwork0.19195 ---
obs0.19375 33373 99.72 %-
all-33373 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 16.044 Å2
Baniso -1Baniso -2Baniso -3
1-0.05 Å20 Å20 Å2
2--0.06 Å20 Å2
3----0.11 Å2
Refinement stepCycle: LAST / Resolution: 1.65→35.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2252 0 23 174 2449
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0212338
X-RAY DIFFRACTIONr_bond_other_d0.0010.021555
X-RAY DIFFRACTIONr_angle_refined_deg1.3371.9823181
X-RAY DIFFRACTIONr_angle_other_deg1.05633787
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4385283
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.95323.6100
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.46315374
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.0621510
X-RAY DIFFRACTIONr_chiral_restr0.1460.2340
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.022619
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02483
X-RAY DIFFRACTIONr_nbd_refined0.2160.2479
X-RAY DIFFRACTIONr_nbd_other0.1850.21594
X-RAY DIFFRACTIONr_nbtor_refined0.1820.21148
X-RAY DIFFRACTIONr_nbtor_other0.0830.21102
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1220.2102
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.130.26
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2190.240
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2280.211
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.881.51461
X-RAY DIFFRACTIONr_mcbond_other0.1731.5576
X-RAY DIFFRACTIONr_mcangle_it1.39222276
X-RAY DIFFRACTIONr_scbond_it2.09331101
X-RAY DIFFRACTIONr_scangle_it3.2224.5905
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.65→1.691 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.306 138 -
Rwork0.245 2375 -
obs--98.2 %

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