7E0A

X-ray structure of human PPARgamma ligand binding domain-saroglitazar co-crystals obtained by co-crystallization

Summary for 7E0A

• Entry DOI: 10.2210/pdb7e0a/pdb
• Descriptor: Isoform 2 of Peroxisome proliferator-activated receptor gamma, (2S)-2-ethoxy-3-[4-[2-[2-methyl-5-(4-methylsulfanylphenyl)pyrrol-1-yl]ethoxy]phenyl]propanoic acid (3 entities in total)
• Functional Keywords: nuclear receptor, protein-ligand complex, ppar, transcription
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 32417.65

Authors

Kamata, S.,Honda, A.,Uchii, K.,Machida, Y.,Oyama, T.,Ishii, I. (deposition date: 2021-01-27, release date: 2021-09-08, Last modification date: 2023-11-29)

Primary citation

Honda, A.,Kamata, S.,Satta, C.,Machida, Y.,Uchii, K.,Terasawa, K.,Nemoto, A.,Oyama, T.,Ishii, I.
Structural Basis for Anti-non-alcoholic Fatty Liver Disease and Diabetic Dyslipidemia Drug Saroglitazar as a PPAR alpha / gamma Dual Agonist.
Biol.Pharm.Bull., 44:1210-1219, 2021

PubMed Abstract: Peroxisome proliferator-activated receptors (PPARs) are nuclear receptor-type transcription factors that consist of three subtypes (α, γ, and β/δ) with distinct functions and PPAR dual/pan agonists are expected to be the next generation of drugs for metabolic diseases. Saroglitazar is the first clinically approved PPARα/γ dual agonist for treatment of diabetic dyslipidemia and is currently in clinical trials to treat non-alcoholic fatty liver disease (NAFLD); however, the structural information of its interaction with PPARα/γ remains unknown. We recently revealed the high-resolution co-crystal structure of saroglitazar and the PPARα-ligand binding domain (LBD) through X-ray crystallography, and in this study, we report the structure of saroglitazar and the PPARγ-LBD. Saroglitazar was located at the center of "Y"-shaped PPARγ-ligand-binding pocket (LBP), just as it was in the respective region of PPARα-LBP. Its carboxylic acid was attached to four amino acids (Ser289/His323/His449/Thr473), which contributes to the stabilization of Activating Function-2 helix 12, and its phenylpyrrole moiety was rotated 121.8 degrees in PPARγ-LBD from that in PPARα-LBD to interact with Phe264. PPARδ-LBD has the consensus four amino acids (Thr253/His287/His413/Tyr437) towards the carboxylic acids of its ligands, but it seems to lack sufficient space to accept saroglitazar because of the steric hindrance between the Trp228 or Arg248 residue of PPARδ-LBD and its methylthiophenyl moiety. Accordingly, in a coactivator recruitment assay, saroglitazar activated PPARα-LBD and PPARγ-LBD but not PPARδ-LBD, whereas glycine substitution of either Trp228, Arg248, or both of PPARδ-LBD conferred saroglitazar concentration-dependent activation. Our findings may be valuable in the molecular design of PPARα/γ dual or PPARα/γ/δ pan agonists.

PubMed: 34471049
DOI: 10.1248/bpb.b21-00232

Experimental method

X-RAY DIFFRACTION (1.771 Å)