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Yorodumi- PDB-5wal: Identification of an imidazopyridine scaffold to generate potent ... -
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-Basic information
Entry | Database: PDB / ID: 5wal | ||||||
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Title | Identification of an imidazopyridine scaffold to generate potent and selective TYK2 inhibitors that demonstrate activity in an in vivo psoriasis model | ||||||
Components | Non-receptor tyrosine-protein kinase TYK2 | ||||||
Keywords | TRANSFERASE/TRANSFERASE INHIBITOR / Tyk2 / Kinase / Inhibitor / 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 / 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: 2.45 Å | ||||||
Authors | Ultsch, M.H. / Magnuson, S. | ||||||
Citation | Journal: Bioorg. Med. Chem. Lett. / Year: 2017 Title: Identification of an imidazopyridine scaffold to generate potent and selective TYK2 inhibitors that demonstrate activity in an in vivo psoriasis model. Authors: Liang, J. / Van Abbema, A. / Balazs, M. / Barrett, K. / Berezhkovsky, L. / Blair, W.S. / Chang, C. / Delarosa, D. / DeVoss, J. / Driscoll, J. / Eigenbrot, C. / Goodacre, S. / Ghilardi, N. / ...Authors: Liang, J. / Van Abbema, A. / Balazs, M. / Barrett, K. / Berezhkovsky, L. / Blair, W.S. / Chang, C. / Delarosa, D. / DeVoss, J. / Driscoll, J. / Eigenbrot, C. / Goodacre, S. / Ghilardi, N. / MacLeod, C. / Johnson, A. / Bir Kohli, P. / Lai, Y. / Lin, Z. / Mantik, P. / Menghrajani, K. / Nguyen, H. / Peng, I. / Sambrone, A. / Shia, S. / Smith, J. / Sohn, S. / Tsui, V. / Ultsch, M. / Williams, K. / Wu, L.C. / Yang, W. / Zhang, B. / Magnuson, S. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 5wal.cif.gz | 137.3 KB | Display | PDBx/mmCIF format |
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PDB format | pdb5wal.ent.gz | 104.6 KB | Display | PDB format |
PDBx/mmJSON format | 5wal.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 5wal_validation.pdf.gz | 780.9 KB | Display | wwPDB validaton report |
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Full document | 5wal_full_validation.pdf.gz | 782.4 KB | Display | |
Data in XML | 5wal_validation.xml.gz | 13.4 KB | Display | |
Data in CIF | 5wal_validation.cif.gz | 18.4 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/wa/5wal ftp://data.pdbj.org/pub/pdb/validation_reports/wa/5wal | HTTPS FTP |
-Related structure data
Related structure data | 5wevC 3nz0S S: Starting model for refinement C: citing same article (ref.) |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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Unit cell |
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-Components
#1: Protein | Mass: 34748.734 Da / Num. of mol.: 1 Mutation: C936A, Q969A, E971A, K972A, S1016A, C1142A, D1023N 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 |
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#2: Chemical | ChemComp-9ZS / |
#3: Water | ChemComp-HOH / |
-Experimental details
-Experiment
Experiment | Method: X-RAY DIFFRACTION / Number of used crystals: 1 |
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-Sample preparation
Crystal | Density Matthews: 2.05 Å3/Da / Density % sol: 40.12 % / Description: This rods |
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Crystal grow | Temperature: 291 K / Method: vapor diffusion, hanging drop / pH: 6.5 Details: 20-25%(w/v) PEG3350 and 0.2M Mg sulfate, 0.1M MES pH6.5 |
-Data collection
Diffraction | Mean temperature: 100 K |
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Diffraction source | Source: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.979 Å |
Detector | Type: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Dec 15, 2012 |
Radiation | Monochromator: Si(III) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 0.979 Å / Relative weight: 1 |
Reflection | Resolution: 2.45→60.93 Å / Num. obs: 11094 / % possible obs: 100 % / Observed criterion σ(I): 2 / Redundancy: 6.4 % / Biso Wilson estimate: 42 Å2 / Rsym value: 0.128 / Net I/σ(I): 10.7 |
Reflection shell | Resolution: 2.45→2.535 Å / Redundancy: 6.8 % / Num. unique obs: 1068 / Rsym value: 0.631 / % possible all: 100 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: 3NZ0 Resolution: 2.45→60.93 Å / Cor.coef. Fo:Fc: 0.927 / Cor.coef. Fo:Fc free: 0.873 / Rfactor Rfree error: 0.01 / SU R Cruickshank DPI: 0.682 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 1.125 / SU Rfree Blow DPI: 0.286 / SU Rfree Cruickshank DPI: 0.282
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Displacement parameters | Biso mean: 37.46 Å2
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Refine analyze | Luzzati coordinate error obs: 0.28 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: 1 / Resolution: 2.45→60.93 Å
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Refine LS restraints |
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LS refinement shell | Resolution: 2.45→2.68 Å / Rfactor Rfree error: 0 / Total num. of bins used: 6
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Refinement TLS params. | Method: refined / Refine-ID: X-RAY DIFFRACTION
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Refinement TLS group |
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