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

Takuji Oyama, Kenji Toyota, Tsuyoshi Waku, Yuko Hirakawa, Naoko Nagasawa, Jun Ichi Kasuga, Yuichi Hashimoto, Hiroyuki Miyachi, Kosuke Morikawa

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61 Citations (Scopus)


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 PPA Rα and PPA Rγ 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 PPA Rα LBD in complex with an α/δ-selective ligand, TIPP-401, and with a related - specific ligand, TIPP-204, were also determined. The comparison between the two PPA Rα complexes revealed how each ligand exhibits either a dual selective or single specific binding mode.

Original languageEnglish
Pages (from-to)786-795
Number of pages10
JournalActa Crystallographica Section D: Biological Crystallography
Issue number8
Publication statusPublished - 2009
Externally publishedYes


  • Agonists
  • Ligand-binding domains
  • Peroxisome proliferator-activated receptors

ASJC Scopus subject areas

  • Structural Biology


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