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8HUK

X-ray structure of human PPAR alpha ligand binding domain-lanifibranor-SRC1 coactivator peptide co-crystals obtained by soaking

Summary for 8HUK
Entry DOI10.2210/pdb8huk/pdb
DescriptorPeroxisome proliferator-activated receptor alpha, 15-meric peptide from Nuclear receptor coactivator 1, 4-[1-(1,3-benzothiazol-6-ylsulfonyl)-5-chloro-indol-2-yl]butanoic acid (3 entities in total)
Functional Keywordsnuclear receptor, protein-ligand complex, ppar, transcription
Biological sourceHomo sapiens (human)
More
Total number of polymer chains3
Total formula weight63995.20
Authors
Kamata, S.,Ishikawa, R.,Akahane, M.,Honda, A.,Oyama, T.,Ishii, I. (deposition date: 2022-12-24, release date: 2023-08-09, Last modification date: 2023-09-06)
Primary citationKamata, S.,Honda, A.,Ishikawa, R.,Akahane, M.,Fujita, A.,Kaneko, C.,Miyawaki, S.,Habu, Y.,Shiiyama, Y.,Uchii, K.,Machida, Y.,Oyama, T.,Ishii, I.
Functional and Structural Insights into the Human PPAR alpha / delta / gamma Targeting Preferences of Anti-NASH Investigational Drugs, Lanifibranor, Seladelpar, and Elafibranor.
Antioxidants, 12:-, 2023
Cited by
PubMed Abstract: No therapeutic drugs are currently available for nonalcoholic steatohepatitis (NASH) that progresses from nonalcoholic fatty liver via oxidative stress-involved pathways. Three cognate peroxisome proliferator-activated receptor (PPAR) subtypes (PPARα/δ/γ) are considered as attractive targets. Although lanifibranor (PPARα/δ/γ pan agonist) and saroglitazar (PPARα/γ dual agonist) are currently under investigation in clinical trials for NASH, the development of seladelpar (PPARδ-selective agonist), elafibranor (PPARα/δ dual agonist), and many other dual/pan agonists has been discontinued due to serious side effects or little/no efficacies. This study aimed to obtain functional and structural insights into the potency, efficacy, and selectivity against PPARα/δ/γ of three current and past anti-NASH investigational drugs: lanifibranor, seladelpar, and elafibranor. Ligand activities were evaluated by three assays to detect different facets of the PPAR activation: transactivation assay, coactivator recruitment assay, and thermal stability assay. Seven high-resolution cocrystal structures (namely, those of the PPARα/δ/γ-ligand-binding domain (LBD)-lanifibranor, PPARα/δ/γ-LBD-seladelpar, and PPARα-LBD-elafibranor) were obtained through X-ray diffraction analyses, six of which represent the first deposit in the Protein Data Bank. Lanifibranor and seladelpar were found to bind to different regions of the PPARα/δ/γ-ligand-binding pockets and activated all PPAR subtypes with different potencies and efficacies in the three assays. In contrast, elafibranor induced transactivation and coactivator recruitment (not thermal stability) of all PPAR subtypes, but the PPARδ/γ-LBD-elafibranor cocrystals were not obtained. These results illustrate the highly variable PPARα/δ/γ activation profiles and binding modes of these PPAR ligands that define their pharmacological actions.
PubMed: 37627519
DOI: 10.3390/antiox12081523
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2.981 Å)
Structure validation

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