7C6Q

Novel natural PPARalpha agonist with a unique binding mode

Summary for 7C6Q

• Entry DOI: 10.2210/pdb7c6q/pdb
• Descriptor: Peroxisome proliferator-activated receptor alpha, LYS-ILE-LEU-HIS-ARG-LEU-LEU-GLN, 13-methyl[1,3]benzodioxolo[5,6-c][1,3]dioxolo[4,5-i]phenanthridin-13-ium, ... (4 entities in total)
• Functional Keywords: agonist, transcription
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 33354.75

Authors

Tian, S.Y.,Wang, R.,Zheng, W.L.,Li, Y. (deposition date: 2020-05-22, release date: 2021-05-26, Last modification date: 2023-11-29)

Primary citation

Tian, S.,Wang, R.,Chen, S.,He, J.,Zheng, W.,Li, Y.
Structural Basis for PPARs Activation by The Dual PPAR alpha / gamma Agonist Sanguinarine: A Unique Mode of Ligand Recognition.
Molecules, 26:-, 2021

PubMed Abstract: Peroxisome proliferator-activated receptors (PPARs) play crucial roles in glucose and lipid metabolism and inflammation. Sanguinarine is a natural product that is isolated from Sanguinaria Canadensis, a potential therapeutic agent for intervention in chronic diseases. In this study, biochemical and cell-based promoter-reporter gene assays revealed that sanguinarine activated both PPARα and PPARγ, and enhanced their transcriptional activity; thus, sanguinarine was identified as a dual agonist of PPARα/γ. Similar to fenofibrate, sanguinarine upregulates the expression of PPARα-target genes in hepatocytes. Sanguinarine also modulates the expression of key PPARγ-target genes and promotes adipocyte differentiation, but with a lower adipogenic activity compared with rosiglitazone. We report the crystal structure of sanguinarine bound to PPARα, which reveals a unique ligand-binding mode of sanguinarine, dissimilar to the classic Y-shaped binding pocket, which may represent a new pharmacophore that can be optimized for selectively targeting PPARα. Further structural and functional studies uncover the molecular basis for the selectivity of sanguinarine toward PPARα/γ among all three PPARs. In summary, our study identifies a PPARα/γ dual agonist with a unique ligand-binding mode, and provides a promising and viable novel template for the design of dual-targeting PPARs ligands.

PubMed: 34641558
DOI: 10.3390/molecules26196012

Experimental method

X-RAY DIFFRACTION (2.76 Å)