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

作者：Oyama Takuji; Toyota Kenji; Waku Tsuyoshi; Hirakawa Yuko; Nagasawa Naoko; Kasuga Jun ichi; Hashimoto Yuichi; Miyachi Hiroyuki; Morikawa Kosuke^*

来源：Acta Crystallographica Section D-Biological Crystallography, 2009, 65(8): 786-795.

DOI：10.1107/S0907444909015935

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-alkoxy-phenyl) propanoic acid, which exhibit unique agonistic activities. The PPAR alpha and PPAR gamma 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 PPAR delta LBD in complex with an alpha/delta-selective ligand, TIPP-401, and with a related delta-specific ligand, TIPP-204, were also determined. The comparison between the two PPAR delta complexes revealed how each ligand exhibits either a 'dual selective' or 'single specific' binding mode.

• 出版日期2009-8