8RCE

Crystal structure of PPAR alfa Ligand Binding Domain in complex with the ligand LBB78

8RCE の概要

• エントリーDOI: 10.2210/pdb8rce/pdb
• 分子名称: Peroxisome proliferator-activated receptor alpha, (2~{S})-2-(4-naphthalen-1-ylphenoxy)-3-phenyl-propanoic acid (3 entities in total)
• 機能のキーワード: nucelar receptors, ppars, transcription
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 32619.96

構造登録者

Capelli, D.,Montanari, R. (登録日: 2023-12-06, 公開日: 2024-10-16)

主引用文献

Laghezza, A.,Cerchia, C.,Genovese, M.,Montanari, R.,Capelli, D.,Wackerlig, J.,Simic, S.,Falbo, E.,Pecora, L.,Leuci, R.,Brunetti, L.,Piemontese, L.,Tortorella, P.,Biswas, A.,Singh, R.P.,Tambe, S.,Sudeep, C.A.,Pattnaik, A.K.,Jayaprakash, V.,Paoli, P.,Lavecchia, A.,Loiodice, F.
A chemical modification of a peroxisome proliferator-activated receptor pan agonist produced a shift to a new dual alpha/gamma partial agonist endowed with mitochondrial pyruvate carrier inhibition and antidiabetic properties.
Eur.J.Med.Chem., 275:116567-116567, 2024

PubMed Abstract: New analogs of the PPAR pan agonist AL29-26 encompassed ligand (S)-7 showing potent activation of PPARα and -γ subtypes as a partial agonist. In vitro experiments and docking studies in the presence of PPAR antagonists were performed to help interpretation of biological data and investigate the main interactions at the binding sites. Further in vitro experiments showed that (S)-7 induced anti-steatotic effects and enhancement of the glucose uptake. This latter effect could be partially ascribed to a significant inhibition of the mitochondrial pyruvate carrier demonstrating that (S)-7 also acted through insulin-independent mechanisms. In vivo experiments showed that this compound reduced blood glucose and lipid levels in a diabetic mice model displaying no toxicity on bone, kidney, and liver. To our knowledge, this is the first example of dual PPARα/γ partial agonist showing these combined effects representing, therefore, the potential lead of new drugs for treatment of dyslipidemic type 2 diabetes.

PubMed: 38865743
DOI: 10.1016/j.ejmech.2024.116567

実験手法

X-RAY DIFFRACTION (3 Å)