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Yorodumi- PDB-8s9a: Crystal structure of the TYK2 pseudokinase domain in complex with... -
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-Basic information
Entry | Database: PDB / ID: 8s9a | ||||||
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Title | Crystal structure of the TYK2 pseudokinase domain in complex with TAK-279 | ||||||
Components | Non-receptor tyrosine-protein kinase TYK2 | ||||||
Keywords | TRANSFERASE / TYK2 / pseudokinase / JH2 / immunology | ||||||
Function / homology | Function and homology information type III interferon-mediated signaling pathway / interleukin-12 receptor complex / interleukin-23 receptor complex / Interleukin-23 signaling / type 1 angiotensin receptor binding / positive regulation of T-helper 17 type immune response / positive regulation of NK T cell proliferation / interleukin-12-mediated signaling pathway / Interleukin-12 signaling / Interleukin-27 signaling ...type III interferon-mediated signaling pathway / interleukin-12 receptor complex / interleukin-23 receptor complex / Interleukin-23 signaling / type 1 angiotensin receptor binding / positive regulation of T-helper 17 type immune response / positive regulation of NK T cell proliferation / interleukin-12-mediated signaling pathway / Interleukin-12 signaling / Interleukin-27 signaling / IL-6-type cytokine receptor ligand interactions / Interleukin-35 Signalling / positive regulation of natural killer cell proliferation / growth hormone receptor binding / Other interleukin signaling / extrinsic component of plasma membrane / Interleukin-20 family signaling / type I interferon-mediated signaling pathway / Interleukin-6 signaling / MAPK3 (ERK1) activation / positive regulation of interleukin-17 production / Interleukin-10 signaling / MAPK1 (ERK2) activation / 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 / positive regulation of T cell proliferation / Signaling by CSF3 (G-CSF) / 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 / Evasion by RSV of host interferon responses / 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 / 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 / intracellular signal transduction / immune response / protein phosphorylation / SARS-CoV-2 activates/modulates innate and adaptive immune responses / extracellular exosome / ATP binding / nucleus / plasma membrane / cytoplasm / cytosol Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.83 Å | ||||||
Authors | Toms, A.V. / Leit, S. / Greenwood, J.R. / Carriero, S. / Mondal, S. / Abel, R. / Ashwell, M. / Blanchette, H. / Boyles, N. / Cartwright, M. ...Toms, A.V. / Leit, S. / Greenwood, J.R. / Carriero, S. / Mondal, S. / Abel, R. / Ashwell, M. / Blanchette, H. / Boyles, N. / Cartwright, M. / Collis, A. / Feng, S. / Ghanakota, P. / Harriman, G.C. / Hosagrahara, V. / Kaila, N. / Kapeller, R. / Rafi, S. / Romero, D.L. / Tarantino, P. / Timaniya, J. / Wester, R.T. / Westlin, W. / Srivastava, B. / Miao, W. / Tummino, P. / McElwee, J.J. / Edmondson, S.D. / Massee, C.E. | ||||||
Funding support | 1items
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Citation | Journal: J.Med.Chem. / Year: 2023 Title: Discovery of a Potent and Selective Tyrosine Kinase 2 Inhibitor: TAK-279. Authors: Leit, S. / Greenwood, J. / Carriero, S. / Mondal, S. / Abel, R. / Ashwell, M. / Blanchette, H. / Boyles, N.A. / Cartwright, M. / Collis, A. / Feng, S. / Ghanakota, P. / Harriman, G.C. / ...Authors: Leit, S. / Greenwood, J. / Carriero, S. / Mondal, S. / Abel, R. / Ashwell, M. / Blanchette, H. / Boyles, N.A. / Cartwright, M. / Collis, A. / Feng, S. / Ghanakota, P. / Harriman, G.C. / Hosagrahara, V. / Kaila, N. / Kapeller, R. / Rafi, S.B. / Romero, D.L. / Tarantino, P.M. / Timaniya, J. / Toms, A.V. / Wester, R.T. / Westlin, W. / Srivastava, B. / Miao, W. / Tummino, P. / McElwee, J.J. / Edmondson, S.D. / Masse, C.E. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8s9a.cif.gz | 342.4 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8s9a.ent.gz | 279.1 KB | Display | PDB format |
PDBx/mmJSON format | 8s9a.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8s9a_validation.pdf.gz | 1.3 MB | Display | wwPDB validaton report |
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Full document | 8s9a_full_validation.pdf.gz | 1.4 MB | Display | |
Data in XML | 8s9a_validation.xml.gz | 38.8 KB | Display | |
Data in CIF | 8s9a_validation.cif.gz | 55.3 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/s9/8s9a ftp://data.pdbj.org/pub/pdb/validation_reports/s9/8s9a | HTTPS FTP |
-Related structure data
Related structure data | 8s98C 8s99C C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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2 |
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3 |
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Unit cell |
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-Components
#1: Protein | Mass: 32988.441 Da / Num. of mol.: 3 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 | #3: Chemical | ChemComp-ACT / #4: Chemical | ChemComp-EDO / #5: Water | ChemComp-HOH / | Has ligand of interest | Y | |
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-Experimental details
-Experiment
Experiment | Method: X-RAY DIFFRACTION / Number of used crystals: 1 |
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-Sample preparation
Crystal | Density Matthews: 2.16 Å3/Da / Density % sol: 43.18 % |
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Crystal grow | Temperature: 298 K / Method: vapor diffusion Details: The purified protein was used in crystallization trials employing both, a standard screen with approximately 1200 different conditions, as well as crystallization conditions identified using ...Details: The purified protein was used in crystallization trials employing both, a standard screen with approximately 1200 different conditions, as well as crystallization conditions identified using literature data. Conditions initially obtained have been optimized using standard strategies, systematically varying parameters critically influencing crystallization, such as temperature, protein concentration, drop ratio, and others. These conditions were also refined by systematically varying pH or precipitant concentrations |
-Data collection
Diffraction | Mean temperature: 100 K / Serial crystal experiment: N |
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Diffraction source | Source: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å |
Detector | Type: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 12, 2018 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 1 Å / Relative weight: 1 |
Reflection | Resolution: 1.83→91.75 Å / Num. obs: 74066 / % possible obs: 96.1 % / Redundancy: 2.9 % / Rrim(I) all: 0.067 / Rsym value: 0.055 / Net I/σ(I): 15.93 |
Reflection shell | Resolution: 1.83→2.08 Å / Redundancy: 2.9 % / Mean I/σ(I) obs: 2.97 / Num. unique obs: 23317 / Rrim(I) all: 0.514 / Rsym value: 0.421 / % possible all: 96.1 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.83→45.92 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.941 / SU B: 6.675 / SU ML: 0.101 / Cross valid method: THROUGHOUT / ESU R: 0.14 / ESU R Free: 0.132 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
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Solvent computation | Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 25.003 Å2
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Refinement step | Cycle: 1 / Resolution: 1.83→45.92 Å
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