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Yorodumi- PDB-8b94: Crystal structure of PPARG and NCOR2 with BAY-5516, an inverse agonist -
+Open data
-Basic information
Entry | Database: PDB / ID: 8b94 | ||||||
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Title | Crystal structure of PPARG and NCOR2 with BAY-5516, an inverse agonist | ||||||
Components |
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Keywords | TRANSCRIPTION / nuclear hormone receptor transcription factor | ||||||
Function / homology | Function and homology information Loss of MECP2 binding ability to the NCoR/SMRT complex / negative regulation of androgen receptor signaling pathway / regulation of cellular ketone metabolic process / nuclear glucocorticoid receptor binding / prostaglandin receptor activity / regulation of cholesterol transporter activity / negative regulation of connective tissue replacement involved in inflammatory response wound healing / negative regulation of receptor signaling pathway via STAT / Notch binding / MECP2 regulates transcription factors ...Loss of MECP2 binding ability to the NCoR/SMRT complex / negative regulation of androgen receptor signaling pathway / regulation of cellular ketone metabolic process / nuclear glucocorticoid receptor binding / prostaglandin receptor activity / regulation of cholesterol transporter activity / negative regulation of connective tissue replacement involved in inflammatory response wound healing / negative regulation of receptor signaling pathway via STAT / Notch binding / MECP2 regulates transcription factors / negative regulation of extracellular matrix assembly / negative regulation of vascular endothelial cell proliferation / negative regulation of cellular response to transforming growth factor beta stimulus / negative regulation of cardiac muscle hypertrophy in response to stress / arachidonic acid binding / positive regulation of low-density lipoprotein receptor activity / positive regulation of adiponectin secretion / lipoprotein transport / negative regulation of sequestering of triglyceride / macrophage derived foam cell differentiation / positive regulation of vascular associated smooth muscle cell apoptotic process / DNA binding domain binding / STAT family protein binding / positive regulation of fatty acid metabolic process / response to lipid / negative regulation of SMAD protein signal transduction / NR1H2 & NR1H3 regulate gene expression to control bile acid homeostasis / Notch-HLH transcription pathway / LBD domain binding / negative regulation of type II interferon-mediated signaling pathway / negative regulation of cholesterol storage / E-box binding / alpha-actinin binding / lipid homeostasis / negative regulation of vascular associated smooth muscle cell proliferation / R-SMAD binding / monocyte differentiation / negative regulation of macrophage derived foam cell differentiation / cellular response to low-density lipoprotein particle stimulus / negative regulation of lipid storage / negative regulation of blood vessel endothelial cell migration / Regulation of MECP2 expression and activity / estrous cycle / negative regulation of BMP signaling pathway / white fat cell differentiation / negative regulation of mitochondrial fission / positive regulation of cholesterol efflux / positive regulation of fat cell differentiation / retinoic acid receptor signaling pathway / negative regulation of osteoblast differentiation / positive regulation of DNA binding / cell fate commitment / BMP signaling pathway / long-chain fatty acid transport / nuclear retinoid X receptor binding / negative regulation of signaling receptor activity / cell maturation / regulation of cellular response to insulin stimulus / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / response to organonitrogen compound / epithelial cell differentiation / positive regulation of adipose tissue development / peroxisome proliferator activated receptor signaling pathway / transcription repressor complex / lactation / Regulation of lipid metabolism by PPARalpha / hormone-mediated signaling pathway / cerebellum development / negative regulation of angiogenesis / response to nutrient / fatty acid metabolic process / SUMOylation of transcription cofactors / negative regulation of miRNA transcription / placenta development / negative regulation of MAP kinase activity / Regulation of PTEN gene transcription / transcription coregulator binding / HDACs deacetylate histones / negative regulation of smooth muscle cell proliferation / Downregulation of SMAD2/3:SMAD4 transcriptional activity / peptide binding / negative regulation of transforming growth factor beta receptor signaling pathway / SUMOylation of intracellular receptors / mRNA transcription by RNA polymerase II / regulation of circadian rhythm / lipid metabolic process / PPARA activates gene expression / Cytoprotection by HMOX1 / NOTCH1 Intracellular Domain Regulates Transcription / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / nuclear matrix / regulation of blood pressure / DNA-binding transcription repressor activity, RNA polymerase II-specific / negative regulation of inflammatory response / positive regulation of miRNA transcription / Transcriptional regulation of white adipocyte differentiation / HCMV Early Events / Nuclear Receptor transcription pathway / cellular response to insulin stimulus Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.55 Å | ||||||
Authors | Friberg, A. / Orsi, D.L. / Pook, E. / Siegel, S. / Lemke, C.T. / Stellfeld, T. / Puetter, V. / Goldstein, J. | ||||||
Funding support | 1items
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Citation | Journal: Bioorg.Med.Chem. / Year: 2022 Title: Discovery and characterization of orally bioavailable 4-chloro-6-fluoroisophthalamides as covalent PPARG inverse-agonists. Authors: Orsi, D.L. / Ferrara, S.J. / Siegel, S. / Friberg, A. / Bouche, L. / Pook, E. / Lienau, P. / Bluck, J.P. / Lemke, C.T. / Akcay, G. / Stellfeld, T. / Meyer, H. / Putter, V. / Holton, S.J. / ...Authors: Orsi, D.L. / Ferrara, S.J. / Siegel, S. / Friberg, A. / Bouche, L. / Pook, E. / Lienau, P. / Bluck, J.P. / Lemke, C.T. / Akcay, G. / Stellfeld, T. / Meyer, H. / Putter, V. / Holton, S.J. / Korr, D. / Jerchel-Furau, I. / Pantelidou, C. / Strathdee, C.A. / Meyerson, M. / Eis, K. / Goldstein, J.T. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8b94.cif.gz | 129.8 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8b94.ent.gz | 98.4 KB | Display | PDB format |
PDBx/mmJSON format | 8b94.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/b9/8b94 ftp://data.pdbj.org/pub/pdb/validation_reports/b9/8b94 | HTTPS FTP |
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-Related structure data
Related structure data | 8b8wC 8b8xC 8b8yC 8b8zC 8b90C 8b91C 8b92C 8b93C 8b95C 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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Unit cell |
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-Components
#1: Protein | Mass: 31862.994 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: PPARG, NR1C3 / Production host: Escherichia coli (E. coli) / References: UniProt: P37231 #2: Protein/peptide | Mass: 2638.073 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q9Y618 #3: Chemical | #4: 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: 2.28 Å3/Da / Density % sol: 46.08 % |
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Crystal grow | Temperature: 293 K / Method: vapor diffusion, sitting drop / Details: PEG 3350 20%, HCOOK 0.2 M |
-Data collection
Diffraction | Mean temperature: 100 K / Serial crystal experiment: N |
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Diffraction source | Source: SYNCHROTRON / Site: PETRA III, EMBL c/o DESY / Beamline: P14 (MX2) / Wavelength: 0.9762 Å |
Detector | Type: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Dec 1, 2021 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 0.9762 Å / Relative weight: 1 |
Reflection | Resolution: 1.55→60.63 Å / Num. obs: 89998 / % possible obs: 97.8 % / Redundancy: 13 % / CC1/2: 0.999 / Rrim(I) all: 0.067 / Net I/σ(I): 20.1 |
Reflection shell | Resolution: 1.55→1.65 Å / Redundancy: 13.5 % / Mean I/σ(I) obs: 1.2 / Num. unique obs: 14651 / CC1/2: 0.504 / Rrim(I) all: 2.348 / % possible all: 99.7 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: internal Resolution: 1.55→54.1 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.95 / SU B: 2.426 / SU ML: 0.082 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.089 / ESU R Free: 0.089 / Stereochemistry target values: MAXIMUM LIKELIHOOD Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
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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 max: 106.66 Å2 / Biso mean: 33.446 Å2 / Biso min: 17.51 Å2
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Refinement step | Cycle: final / Resolution: 1.55→54.1 Å
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Refine LS restraints |
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LS refinement shell | Resolution: 1.551→1.591 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
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