Functional and Structural Insights into Human PPARα/δ/γ Subtype Selectivity of Bezafibrate, Fenofibric Acid, and Pemafibrate
Abstract
:1. Introduction
2. Results
2.1. Fibrates Induce Transactivation of Gene Expression via PPARα/δ/γ-LBD
2.2. Fibrates Induce PPARγ Coactivator 1α (PGC1α) or Steroid Receptor Coactivator 1 (SRC1) Recruitment via PPARα/δ/γ-LBD
2.3. Fibrates Induce the Thermostability of PPARα/δ/γ-LBD
2.4. Structures of the PPARα/δ/γ-LBD–Bezafibrate Complexes
2.5. Structures of the PPARα/γ-LBD–Fenofibric Acid Complexes
2.6. Structures of the PPARα/δ/γ-LBD–Pemafibrate Complexes
2.7. Various Binding Modes to PPARα/δ/γ-LBD Pockets
3. Discussion
4. Materials and Methods
4.1. PPAR Activation Assay 1: Transactivation Assay
4.2. Recombinant PPARα/δ/γ-LBD Expression and Purification
4.3. PPAR Activation Assay 2: PGC1α/SRC1 Coactivator Recruitment Assay
4.4. PPAR Activation Assay 3: Thermostability Assay Using CD Spectroscopy
4.5. Cocrystallization of PPARδ/γ-LBD with the Three Fibrates
4.6. X-ray Diffraction: Data Collection and Model Refinement
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Honda, A.; Kamata, S.; Akahane, M.; Machida, Y.; Uchii, K.; Shiiyama, Y.; Habu, Y.; Miyawaki, S.; Kaneko, C.; Oyama, T.; et al. Functional and Structural Insights into Human PPARα/δ/γ Subtype Selectivity of Bezafibrate, Fenofibric Acid, and Pemafibrate. Int. J. Mol. Sci. 2022, 23, 4726. https://doi.org/10.3390/ijms23094726
Honda A, Kamata S, Akahane M, Machida Y, Uchii K, Shiiyama Y, Habu Y, Miyawaki S, Kaneko C, Oyama T, et al. Functional and Structural Insights into Human PPARα/δ/γ Subtype Selectivity of Bezafibrate, Fenofibric Acid, and Pemafibrate. International Journal of Molecular Sciences. 2022; 23(9):4726. https://doi.org/10.3390/ijms23094726
Chicago/Turabian StyleHonda, Akihiro, Shotaro Kamata, Makoto Akahane, Yui Machida, Kie Uchii, Yui Shiiyama, Yuki Habu, Saeka Miyawaki, Chihiro Kaneko, Takuji Oyama, and et al. 2022. "Functional and Structural Insights into Human PPARα/δ/γ Subtype Selectivity of Bezafibrate, Fenofibric Acid, and Pemafibrate" International Journal of Molecular Sciences 23, no. 9: 4726. https://doi.org/10.3390/ijms23094726