Adaptability and selectivity of human peroxisome proliferator-activated receptor (PPAR) pan agonists revealed from crystal structures

Journal Article · Sat Aug 01 04:00:00 EDT 2009 · Acta Crystallographica. Section D: Biological Crystallography

DOI:https://doi.org/10.1107/S0907444909015935· OSTI ID:22347948

Oyama, Takuji; Toyota, Kenji; Waku, Tsuyoshi; Hirakawa, Yuko; Nagasawa, Naoko ^[1]; Kasuga, Jun-ichi; Hashimoto, Yuichi; Miyachi, Hiroyuki ^[2]; Morikawa, Kosuke ^[1]

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1. The Takara Bio Endowed Division, Department of Biomolecular Recognition, Institute for Protein Research, Osaka University, Open Laboratories of Advanced Bioscience and Biotechnology, 6-2-3 Furuedai, Suita, Osaka 565-0874 (Japan)
2. Institute of Molecular and Cellular Biosciences, The University of Tokyo, Yayoi, Bunkyo-ku, Tokyo 113-0032 (Japan)

The structures of the ligand-binding domains (LBDs) of human peroxisome proliferator-activated receptors (PPARα, PPARγ and PPARδ) in complexes with a pan agonist, an α/δ dual agonist and a PPARδ-specific agonist were determined. The results explain how each ligand is recognized by the PPAR LBDs at an atomic level. Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear hormone receptor family, which is defined as transcriptional factors that are activated by the binding of ligands to their ligand-binding domains (LBDs). Although the three PPAR subtypes display different tissue distribution patterns and distinct pharmacological profiles, they all are essentially related to fatty-acid and glucose metabolism. Since the PPARs share similar three-dimensional structures within the LBDs, synthetic ligands which simultaneously activate two or all of the PPARs could be potent candidates in terms of drugs for the treatment of abnormal metabolic homeostasis. The structures of several PPAR LBDs were determined in complex with synthetic ligands, derivatives of 3-(4-alkoxyphenyl)propanoic acid, which exhibit unique agonistic activities. The PPARα and PPARγ LBDs were complexed with the same pan agonist, TIPP-703, which activates all three PPARs and their crystal structures were determined. The two LBD–ligand complex structures revealed how the pan agonist is adapted to the similar, but significantly different, ligand-binding pockets of the PPARs. The structures of the PPARδ LBD in complex with an α/δ-selective ligand, TIPP-401, and with a related δ-specific ligand, TIPP-204, were also determined. The comparison between the two PPARδ complexes revealed how each ligand exhibits either a ‘dual selective’ or ‘single specific’ binding mode.

• OSTI ID: 22347948
• Journal Information: Acta Crystallographica. Section D: Biological Crystallography, Journal Name: Acta Crystallographica. Section D: Biological Crystallography Journal Issue: Pt 8 Vol. 65; ISSN ABCRE6; ISSN 0907-4449
• Country of Publication: Denmark
• Language: English

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