7WGL

X-ray structure of human PPAR delta ligand binding domain-bezafibrate co-crystals obtained by co-crystallization

Summary for 7WGL

• Entry DOI: 10.2210/pdb7wgl/pdb
• Descriptor: Peroxisome proliferator-activated receptor delta, octyl beta-D-glucopyranoside, 2-[P-[2-P-CHLOROBENZAMIDO)ETHYL]PHENOXY]-2-METHYLPROPIONIC ACID, ... (4 entities in total)
• Functional Keywords: nuclear receptor, protein-ligand complex, ppar, transcription
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 64363.67

Authors

Kamata, S.,Honda, A.,Machida, Y.,Uchii, K.,Shiiyama, Y.,Masuda, R.,Oyama, T.,Ishii, I. (deposition date: 2021-12-28, release date: 2022-05-25, Last modification date: 2023-11-29)

Primary citation

Honda, A.,Kamata, S.,Akahane, M.,Machida, Y.,Uchii, K.,Shiiyama, Y.,Habu, Y.,Miyawaki, S.,Kaneko, C.,Oyama, T.,Ishii, I.
Functional and Structural Insights into Human PPAR alpha / delta / gamma Subtype Selectivity of Bezafibrate, Fenofibric Acid, and Pemafibrate.
Int J Mol Sci, 23:-, 2022

PubMed Abstract: Among the agonists against three peroxisome proliferator-activated receptor (PPAR) subtypes, those against PPARα (fibrates) and PPARγ (glitazones) are currently used to treat dyslipidemia and type 2 diabetes, respectively, whereas PPARδ agonists are expected to be the next-generation metabolic disease drug. In addition, some dual/pan PPAR agonists are currently being investigated via clinical trials as one of the first curative drugs against nonalcoholic fatty liver disease (NAFLD). Because PPARα/δ/γ share considerable amino acid identity and three-dimensional structures, especially in ligand-binding domains (LBDs), clinically approved fibrates, such as bezafibrate, fenofibric acid, and pemafibrate, could also act on PPARδ/γ when used as anti-NAFLD drugs. Therefore, this study examined their PPARα/δ/γ selectivity using three independent assays-a dual luciferase-based GAL4 transactivation assay for COS-7 cells, time-resolved fluorescence resonance energy transfer-based coactivator recruitment assay, and circular dichroism spectroscopy-based thermostability assay. Although the efficacy and efficiency highly varied between agonists, assay types, and PPAR subtypes, the three fibrates, except fenofibric acid that did not affect PPARδ-mediated transactivation and coactivator recruitment, activated all PPAR subtypes in those assays. Furthermore, we aimed to obtain cocrystal structures of PPARδ/γ-LBD and the three fibrates via X-ray diffraction and versatile crystallization methods, which we recently used to obtain 34 structures of PPARα-LBD cocrystallized with 17 ligands, including the fibrates. We herein reveal five novel high-resolution structures of PPARδ/γ-bezafibrate, PPARγ-fenofibric acid, and PPARδ/γ-pemafibrate, thereby providing the molecular basis for their application beyond dyslipidemia treatment.

PubMed: 35563117
DOI: 10.3390/ijms23094726

Experimental method

X-RAY DIFFRACTION (2.091 Å)