3SP9

Structural basis for iloprost as a dual PPARalpha/delta agonist

Summary for 3SP9

• Entry DOI: 10.2210/pdb3sp9/pdb
• Related: 3SP6
• Descriptor: Peroxisome proliferator-activated receptor delta, (5E)-5-[(3aS,4R,5R,6aS)-5-hydroxy-4-[(1E,3S,4R)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl]hexahydropentalen-2(1H)-ylidene]pentanoic acid (3 entities in total)
• Functional Keywords: nuclear receptor lbd, nuclear receptor fold, ligand binding, gene transcription, drug binding, transcription
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: Q03181
• Total number of polymer chains: 2
• Total formula weight: 65179.78

Authors

Rong, H.,Li, Y. (deposition date: 2011-07-01, release date: 2011-07-20, Last modification date: 2024-02-28)

Primary citation

Jin, L.,Lin, S.,Rong, H.,Zheng, S.,Jin, S.,Wang, R.,Li, Y.
Structural basis for iloprost as a dual peroxisome proliferator-activated receptor alpha/delta agonist.
J.Biol.Chem., 286:31473-31479, 2011

PubMed 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 PPARα ligand-binding domain and PPARδ 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 PPARα/δ by this prostacyclin analog. In addition to conserved contacts for all PPARα 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-PPARα/δ 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.

PubMed: 21775429
DOI: 10.1074/jbc.M111.266023

Experimental method

X-RAY DIFFRACTION (2.3 Å)