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- PDB-7uyu: Crystal structure of TYK2 kinase domain in complex with compound 30 -

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Basic information

Entry
Database: PDB / ID: 7uyu
TitleCrystal structure of TYK2 kinase domain in complex with compound 30
ComponentsNon-receptor tyrosine-protein kinase TYK2
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / non-receptor tyrosine-protein kinase 2 / TRANSFERASE-TRANSFERASE INHIBITOR complex
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 / 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
Chem-OV0 / Non-receptor tyrosine-protein kinase TYK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.05 Å
AuthorsToms, A.V. / Leit, S. / Greenwood, J.R. / Mondal, S. / Carriero, S. / Dahlgren, M. / Harriman, G.C. / Kennedy-Smith, J.J. / Kapeller, R. / Lawson, J.P. ...Toms, A.V. / Leit, S. / Greenwood, J.R. / Mondal, S. / Carriero, S. / Dahlgren, M. / Harriman, G.C. / Kennedy-Smith, J.J. / Kapeller, R. / Lawson, J.P. / Romero, D.L. / Shelley, M. / Wester, R.T. / Westlin, W. / Mc Elwee, J.J. / Miao, W. / Edmondson, S.D. / Massee, C.E.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2022
Title: Potent and selective TYK2-JH1 inhibitors highly efficacious in rodent model of psoriasis.
Authors: Leit, S. / Greenwood, J.R. / Mondal, S. / Carriero, S. / Dahlgren, M. / Harriman, G.C. / Kennedy-Smith, J.J. / Kapeller, R. / Lawson, J.P. / Romero, D.L. / Toms, A.V. / Shelley, M. / Wester, ...Authors: Leit, S. / Greenwood, J.R. / Mondal, S. / Carriero, S. / Dahlgren, M. / Harriman, G.C. / Kennedy-Smith, J.J. / Kapeller, R. / Lawson, J.P. / Romero, D.L. / Toms, A.V. / Shelley, M. / Wester, R.T. / Westlin, W. / McElwee, J.J. / Miao, W. / Edmondson, S.D. / Masse, C.E.
History
DepositionMay 7, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 24, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 6, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_entry_details / pdbx_modification_feature
Item: _pdbx_entry_details.has_protein_modification

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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)34,1723
Polymers33,6431
Non-polymers5282
Water99155
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)36.174, 74.117, 104.788
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 33643.371 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TYK2 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P29597, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-OV0 / 2-(2,6-difluorophenyl)-4-[4-(pyrrolidine-1-carbonyl)anilino]-5H-pyrrolo[3,4-b]pyridin-5-one


Mass: 432.422 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H18F2N4O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 55 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
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: 2.16 Å3/Da / Density % sol: 43.1 %
Crystal growTemperature: 291 K / Method: vapor diffusion
Details: Crystals of human TYK2 in complex with the ligand were prepared according to established protocols

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.999999701977 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 15, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.999999701977 Å / Relative weight: 1
ReflectionResolution: 2.05→60.51 Å / Num. obs: 17936 / % possible obs: 97.6 % / Redundancy: 3.9 % / Rmerge(I) obs: 0.045 / Net I/σ(I): 18.76
Reflection shellResolution: 2.05→2.3 Å / Redundancy: 3.6 % / Mean I/σ(I) obs: 3.11 / Num. unique obs: 4921 / Rrim(I) all: 0.515 / Rsym value: 0.435 / % possible all: 93.6

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
XSCALEdata scaling
PHASERphasing
REFMAC5.8.0049refinement
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: NONE

Resolution: 2.05→60.51 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.935 / SU B: 16.195 / SU ML: 0.208 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.264 / ESU R Free: 0.204 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2566 1757 9.9 %RANDOM
Rwork0.2241 ---
obs0.2274 16064 97.03 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 149.41 Å2 / Biso mean: 53.555 Å2 / Biso min: 19.05 Å2
Baniso -1Baniso -2Baniso -3
1--0.56 Å2-0 Å20 Å2
2---1.21 Å20 Å2
3---1.77 Å2
Refinement stepCycle: final / Resolution: 2.05→60.51 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2099 0 37 55 2191
Biso mean--61 42.82 -
Num. residues----269
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0192205
X-RAY DIFFRACTIONr_bond_other_d0.0010.022036
X-RAY DIFFRACTIONr_angle_refined_deg1.3691.9923003
X-RAY DIFFRACTIONr_angle_other_deg2.61434643
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.735266
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.42722.98987
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.80515332
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.0921510
X-RAY DIFFRACTIONr_chiral_restr0.0760.2325
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0212454
X-RAY DIFFRACTIONr_gen_planes_other0.0040.02519
LS refinement shellResolution: 2.05→2.104 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.359 119 -
Rwork0.349 1113 -
all-1232 -
obs--92.77 %
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)
16.3559-2.03630.04814.74661.68964.62450.0535-0.8060.30130.7257-0.03090.2066-0.4114-0.3494-0.02270.438-0.0117-0.02070.3159-0.05030.51057.55212.099-6.16
23.5030.15830.35514.5502-0.08141.80190.07290.0523-0.05770.0586-0.1215-0.09130.01320.02150.04870.00510.0102-0.00390.0435-0.01320.401712.945-8.258-21.193
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A889 - 979
2X-RAY DIFFRACTION2A983 - 1177

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