6kxy
Human PPAR alpha ligand binding domain in complex with a synthetic agonist (compound B)
Structural highlights
FunctionPPARA_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 PubMedSmall-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 AlsoReferences
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