Structural basis for iloprost as a dual peroxisome proliferator-activated receptor alpha/delta agonist.

ABSTRACT: 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? ligand-binding domain and PPAR? 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?/? by this prostacyclin analog. In addition to conserved contacts for all PPAR? 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?/? 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.

SUBMITTER: Jin L 

PROVIDER: S-EPMC3173080 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature