Structural Basis for Iloprost as a Dual Peroxisome Proliferator-activated Receptor alpha/delta Agonist
- 生命科学－已发表论文 
Iloprost is a prostacyclin analog that has been used to treat many vascular conditions. Peroxisome proliferator-activated receptors (PPARs) are ligand-regulated transcription factors with various important biological effects such as metabolic and cardiovascular physiology. Here, we report the crystal structures of the PPAR alpha ligand-binding domain and PPAR delta ligand-binding domain bound to iloprost, thus providing unambiguous evidence for the direct interaction between iloprost and PPARs and a structural basis for the recognition of PPAR alpha/delta by this prostacyclin analog. In addition to conserved contacts for all PPAR alpha ligands, iloprost also initiates several specific interactions with PPARs using its unique structural groups. Structural and functional studies of receptor-ligand interactions reveal strong functional correlations of the iloprost-PPAR alpha/delta interactions as well as the molecular basis of PPAR subtype selectivity toward iloprost ligand. As such, the structural mechanism may provide a more rational template for designing novel compounds targeting PPARs with more favorable pharmacologic impact based on existing iloprost drugs.
CitationJ Biol Chem. 2011 Sep 9;286(36):31473-9.