Department of Biotechnology, Faculty of Life and Environmental Sciences, University of Yamanashi, Japan.
Lead Exploration Unit, Drug Discovery Initiative, The University of Tokyo, Japan.
Acta Crystallogr F Struct Biol Commun. 2022 Feb 1;78(Pt 2):81-87. doi: 10.1107/S2053230X22000449. Epub 2022 Jan 31.
Peroxisome proliferator-activated receptor δ (PPARδ) is a member of the nuclear receptor family and regulates glucose and lipid homeostasis in a ligand-dependent manner. Numerous phenylpropanoic acid derivatives targeting three PPAR subtypes (PPARα, PPARγ and PPARδ) have been developed towards the treatment of serious diseases such as lipid-metabolism disorders. In spite of the increasing attraction of PPARδ as a pharmaceutical target, only a limited number of protein-ligand complex structures are available. Here, four crystal structures of the ligand-binding domain of PPARδ in complexes with phenylpropanoic acid derivatives and a pyridine carboxylic acid derivative are described, including an updated, higher resolution version of a previous studied structure and three novel structures. These structures showed that the ligands were bound in the ligand-binding pocket of the receptor in a similar manner but with minor variations. The results could provide variable structural information for the further design and development of ligands targeting PPARδ.
过氧化物酶体增殖物激活受体 δ（PPARδ）是核受体家族的一员，以配体依赖的方式调节葡萄糖和脂质的动态平衡。已经开发出许多针对三种 PPAR 亚型（PPARα、PPARγ 和 PPARδ）的苯丙酸衍生物，以治疗脂质代谢紊乱等严重疾病。尽管 PPARδ 作为药物靶点的吸引力不断增加，但只有有限数量的蛋白-配体复合物结构可用。在这里，描述了 PPARδ 配体结合域与苯丙酸衍生物和吡啶羧酸衍生物复合物的四个晶体结构，包括之前研究结构的更新、更高分辨率版本和三个新结构。这些结构表明，配体以相似的方式但略有不同的方式结合在受体的配体结合口袋中。这些结果可为进一步设计和开发针对 PPARδ 的配体提供可变的结构信息。
