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- PDB-6ova: Crystal Structure of TYK2 with novel pyrrolidinone inhibitor -

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Basic information

Entry
Database: PDB / ID: 6ova
TitleCrystal Structure of TYK2 with novel pyrrolidinone inhibitor
ComponentsNon-receptor tyrosine-protein kinase TYK2
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Inhibitor / Complex / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


type III interferon-mediated signaling pathway / interleukin-12 receptor complex / interleukin-23 receptor complex / Interleukin-23 signaling / positive regulation of T-helper 17 type immune response / type 1 angiotensin receptor binding / positive regulation of NK T cell proliferation / interleukin-12-mediated signaling pathway / Interleukin-12 signaling / Interleukin-35 Signalling ...type III interferon-mediated signaling pathway / interleukin-12 receptor complex / interleukin-23 receptor complex / Interleukin-23 signaling / positive regulation of T-helper 17 type immune response / type 1 angiotensin receptor binding / positive regulation of NK T cell proliferation / interleukin-12-mediated signaling pathway / Interleukin-12 signaling / Interleukin-35 Signalling / Interleukin-27 signaling / IL-6-type cytokine receptor ligand interactions / growth hormone receptor binding / Other interleukin signaling / extrinsic component of plasma membrane / Interleukin-20 family signaling / Interleukin-6 signaling / type I interferon-mediated signaling pathway / positive regulation of interleukin-17 production / MAPK3 (ERK1) activation / Interleukin-10 signaling / MAPK1 (ERK2) activation / positive regulation of natural killer cell proliferation / cell surface receptor signaling pathway via JAK-STAT / Regulation of IFNA/IFNB signaling / growth hormone receptor signaling pathway via JAK-STAT / type II interferon-mediated signaling pathway / Signaling by CSF3 (G-CSF) / positive regulation of T cell proliferation / non-specific protein-tyrosine kinase / positive regulation of receptor signaling pathway via JAK-STAT / non-membrane spanning protein tyrosine kinase activity / Inactivation of CSF3 (G-CSF) signaling / cytoplasmic side of plasma membrane / cellular response to virus / cytokine-mediated signaling pathway / positive regulation of protein localization to nucleus / Interferon alpha/beta signaling / positive regulation of type II interferon production / protein tyrosine kinase activity / Interleukin-4 and Interleukin-13 signaling / Potential therapeutics for SARS / cell differentiation / cytoskeleton / intracellular signal transduction / immune response / protein phosphorylation / SARS-CoV-2 activates/modulates innate and adaptive immune responses / extracellular exosome / ATP binding / nucleus / plasma membrane / cytosol / cytoplasm
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 / FERM superfamily, second domain / FERM 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 / 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 / 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
Chem-N9G / Non-receptor tyrosine-protein kinase TYK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.5 Å
AuthorsSkene, R.J. / Hoffman, I.D.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2020
Title: Efficient synthesis of tert-butyl 3-cyano-3-cyclopropyl-2-oxopyrrolidine-4-carboxylates: Highly functionalized 2-pyrrolidinone enabling access to novel macrocyclic Tyk2 inhibitors.
Authors: Sasaki, Y. / Tokuhara, H. / Ohba, Y. / Okabe, A. / Nakayama, M. / Nakagawa, H. / Skene, R. / Hoffman, I. / Zou, H. / Yoshida, M.
History
DepositionMay 7, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 12, 2020Provider: repository / Type: Initial release
Revision 1.1Mar 13, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)35,2352
Polymers34,8451
Non-polymers3901
Water90150
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area13410 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.073, 48.073, 475.025
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number178
Space group name H-MP6122

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Components

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


Mass: 34844.863 Da / Num. of mol.: 1 / Fragment: residues 884-1176
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TYK2 / Production host: unidentified baculovirus
References: UniProt: P29597, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-N9G / 6-({4-[(3S)-3-cyano-3-cyclopropyl-2-oxopyrrolidin-1-yl]pyridin-2-yl}amino)-N,N-dimethylpyridine-3-carboxamide


Mass: 390.438 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H22N6O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 50 / 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: 2.5 Å3/Da / Density % sol: 50.74 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6
Details: 15% PEG 5000 MME, and 100 mM Sodium Citrate (pH 6.0)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.976 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Feb 6, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 2.5→50 Å / Num. obs: 12106 / % possible obs: 95.8 % / Redundancy: 9.3 % / Rmerge(I) obs: 0.078 / Χ2: 1.004 / Net I/σ(I): 10.2 / Num. measured all: 112859
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
2.5-2.545.60.2973821.071163.7
2.54-2.596.30.3784531.036176.5
2.59-2.647.60.3614940.961182.6
2.64-2.698.10.3495490.97189.6
2.69-2.758.50.3385910.982199.8
2.75-2.829.30.3376140.9911100
2.82-2.89100.2555891.0181100
2.89-2.9610.20.2496220.9961100
2.96-3.0510.10.1786061.0111100
3.05-3.1510.50.1666001.0061100
3.15-3.2610.30.1496230.9891100
3.26-3.3910.30.1076191.0151100
3.39-3.55100.0746201.0261100
3.55-3.7310.30.0786391.0031100
3.73-3.9710.10.0636371.0021100
3.97-4.279.90.0566291.0111100
4.27-4.79.90.0586570.9891100
4.7-5.389.60.0666661.0131100
5.38-6.789.20.0666931.0541100
6.78-508.20.0338230.973199.8

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation6.54 Å41.95 Å
Translation6.54 Å41.95 Å

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Processing

Software
NameVersionClassification
REFMAC5.8.0238refinement
HKL-2000data scaling
PHASER2.5.1phasing
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.5→24.17 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.944 / SU B: 24.673 / SU ML: 0.253 / SU R Cruickshank DPI: 0.5247 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.531 / ESU R Free: 0.292 / Details: U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2509 574 4.8 %RANDOM
Rwork0.1968 ---
obs0.1995 11364 95.62 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 200.57 Å2 / Biso mean: 73.301 Å2 / Biso min: 40.36 Å2
Baniso -1Baniso -2Baniso -3
1-0.48 Å20.24 Å20 Å2
2--0.48 Å20 Å2
3----1.56 Å2
Refinement stepCycle: final / Resolution: 2.5→24.17 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2227 0 29 50 2306
Biso mean--69.36 67.04 -
Num. residues----273
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0122323
X-RAY DIFFRACTIONr_angle_refined_deg1.3781.6593146
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7395271
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.59121.694124
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.45315401
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.1811515
X-RAY DIFFRACTIONr_chiral_restr0.1060.2283
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.021776
LS refinement shellResolution: 2.504→2.569 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.42 29 -
Rwork0.417 542 -
all-571 -
obs--66.94 %
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)
11.1087-1.0998-0.66361.20511.06783.1310.21460.07350.0864-0.2062-0.1215-0.01180.49270.0243-0.09310.50190.1374-0.01370.1041-0.04340.186626.14-16.325-5.872
20.3387-0.4885-0.40.9502-0.18574.36190.04640.01410.0124-0.1943-0.07240.10430.02760.23670.0260.32510.0248-0.00540.14030.0020.27826.169-9.9054
32.14661.3199-0.52990.85250.09014.8734-0.6288-0.27380.305-0.3603-0.04860.25610.91531.42230.67740.60440.34290.00370.42880.17030.162932.011-25.64518.727
40.03510.0573-0.40690.0977-0.66764.72130.0066-0.0124-0.00560.0031-0.04030.019-0.13910.16750.03370.31970.0068-0.01670.1273-0.04440.306923.754-9.53416.001
50.0135-0.05160.1390.3778-1.22744.5590.0135-0.030.0485-0.18820.0744-0.08350.5653-0.5078-0.08780.3149-0.02740.00350.32030.0180.318216.868-18.35923.99
60.0247-0.03320.14320.1725-0.96375.49090.0109-0.07640.0471-0.06280.0401-0.00650.3973-0.0239-0.0510.21580.0064-0.0140.375-0.06620.230221.471-18.21531.523
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A888 - 933
2X-RAY DIFFRACTION2A942 - 984
3X-RAY DIFFRACTION3A985 - 1008
4X-RAY DIFFRACTION4A1009 - 1059
5X-RAY DIFFRACTION5A1060 - 1110
6X-RAY DIFFRACTION6A1111 - 1175

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