| Structural highlights
Function
PPARA_HUMAN Ligand-activated transcription factor. Key regulator of lipid metabolism. Activated by the endogenous ligand 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (16:0/18:1-GPC). Activated by oleylethanolamide, a naturally occurring lipid that regulates satiety (By similarity). Receptor for peroxisome proliferators such as hypolipidemic drugs and fatty acids. Regulates the peroxisomal beta-oxidation pathway of fatty acids. Functions as transcription activator for the ACOX1 and P450 genes. Transactivation activity requires heterodimerization with RXRA and is antagonized by NR2C2.[1] [2] [3] [4]
Publication Abstract from PubMed
Small-molecule agonism of peroxisome proliferator-activated receptor alpha (PPARalpha), a ligand-activated transcriptional factor involved in regulating fatty acid metabolism, is an important approach for treating dyslipidemia. Here, we determined the structures of the ligand-binding domain (LBD) of PPARalpha in complex with 1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid derivatives, which were recently identified as PPARalpha-selective activators with markedly different structures from those of the well-known PPARalpha agonists fibrates. The crystal structures of the complexes showed that they form a canonical hydrogen-bond network involving helix 12 in the LBD, which is thought to be essential for PPARalpha activation, as also observed for fibrates. However, the phenyl side chain of the compounds occupies a small cavity between Ile272 and Ile354, which is rarely accessed by fibrates. This unique feature may be essential for subtype selectivity and combine with the well-characterized binding mode of fibrates to improve activity. These findings demonstrate the advantage of using 1H-pyrazolo-[3,4-b]pyridine as a skeleton of PPARalpha agonists and provide insight into the design of molecules for treating dyslipidemia.
Structural Basis for PPARalpha Activation by 1H-pyrazolo-[3,4-b]pyridine Derivatives.,Yoshida T, Oki H, Doi M, Fukuda S, Yuzuriha T, Tabata R, Ishimoto K, Kawahara K, Ohkubo T, Miyachi H, Doi T, Tachibana K Sci Rep. 2020 May 6;10(1):7623. doi: 10.1038/s41598-020-64527-x. PMID:32376995[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Sher T, Yi HF, McBride OW, Gonzalez FJ. cDNA cloning, chromosomal mapping, and functional characterization of the human peroxisome proliferator activated receptor. Biochemistry. 1993 Jun 1;32(21):5598-604. PMID:7684926
- ↑ Juge-Aubry CE, Gorla-Bajszczak A, Pernin A, Lemberger T, Wahli W, Burger AG, Meier CA. Peroxisome proliferator-activated receptor mediates cross-talk with thyroid hormone receptor by competition for retinoid X receptor. Possible role of a leucine zipper-like heptad repeat. J Biol Chem. 1995 Jul 28;270(30):18117-22. PMID:7629123
- ↑ Yan ZH, Karam WG, Staudinger JL, Medvedev A, Ghanayem BI, Jetten AM. Regulation of peroxisome proliferator-activated receptor alpha-induced transactivation by the nuclear orphan receptor TAK1/TR4. J Biol Chem. 1998 May 1;273(18):10948-57. PMID:9556573
- ↑ Gorla-Bajszczak A, Juge-Aubry C, Pernin A, Burger AG, Meier CA. Conserved amino acids in the ligand-binding and tau(i) domains of the peroxisome proliferator-activated receptor alpha are necessary for heterodimerization with RXR. Mol Cell Endocrinol. 1999 Jan 25;147(1-2):37-47. PMID:10195690
- ↑ Yoshida T, Oki H, Doi M, Fukuda S, Yuzuriha T, Tabata R, Ishimoto K, Kawahara K, Ohkubo T, Miyachi H, Doi T, Tachibana K. Structural Basis for PPARα Activation by 1H-pyrazolo-[3,4-b]pyridine Derivatives. Sci Rep. 2020 May 6;10(1):7623. PMID:32376995 doi:10.1038/s41598-020-64527-x
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