Abstract
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 language | English |
|---|---|
| Pages (from-to) | 786-795 |
| Number of pages | 10 |
| Journal | Acta Crystallographica Section D: Biological Crystallography |
| Volume | 65 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - 2009 |
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Keywords
- Agonists
- Ligand-binding domains
- Peroxisome proliferator-activated receptors
ASJC Scopus subject areas
- Structural Biology
Cite this
Adaptability and selectivity of human peroxisome proliferator-activated receptor (PPAR) pan agonists revealed from crystal structures. / Oyama, Takuji; Toyota, Kenji; Waku, Tsuyoshi; Hirakawa, Yuko; Nagasawa, Naoko; Kasuga, Jun Ichi; Hashimoto, Yuichi; Miyachi, Hiroyuki; Morikawa, Kosuke.
In: Acta Crystallographica Section D: Biological Crystallography, Vol. 65, No. 8, 2009, p. 786-795.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Adaptability and selectivity of human peroxisome proliferator-activated receptor (PPAR) pan agonists revealed from crystal structures
AU - Oyama, Takuji
AU - Toyota, Kenji
AU - Waku, Tsuyoshi
AU - Hirakawa, Yuko
AU - Nagasawa, Naoko
AU - Kasuga, Jun Ichi
AU - Hashimoto, Yuichi
AU - Miyachi, Hiroyuki
AU - Morikawa, Kosuke
PY - 2009
Y1 - 2009
N2 - 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.
AB - 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.
KW - Agonists
KW - Ligand-binding domains
KW - Peroxisome proliferator-activated receptors
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U2 - 10.1107/S0907444909015935
DO - 10.1107/S0907444909015935
M3 - Article
VL - 65
SP - 786
EP - 795
JO - Acta Crystallographica Section D: Structural Biology
JF - Acta Crystallographica Section D: Structural Biology
SN - 0907-4449
IS - 8
ER -