Different structures of the two peroxisome proliferator-activated receptor gamma (PPARγ) ligand-binding domains in homodimeric complex with partial agonist, but not full agonist

We designed and synthesized acylsulfonamide derivative (3) as a human peroxisome proliferator-activated receptor gamma (hPPAR gamma) partial agonist by structural modification of hPPAR gamma full agonist 1. Co-crystallization of 3 with hPPAR gamma LBD afforded a homodimeric complex, and X-ray crystallographic analysis at 2.1 angstrom resolution showed that one of the LBDs adopts a fully active structure identical with that in the complex of rosiglitazone, a full agonist; however, the other LBD in the complex of 3 exhibits a different (non-fully active) structure. Interestingly, the apo-homodimer contained similar LBD structures. Intrigued by these results, we surveyed reported X-ray crystal structures of partial agonists complexed with hPPAR gamma LBD homodimer, and identified several types of LBD structures distinct from the fully active structure. In contrast, both LBDs in the rosiglitazone complex have the fully active structure. These results suggest hPPAR gamma partial agonists lack the ability to induce fully active LBD. The presence of at least one non-fully active LBD in the agonist complex may be a useful criterion to distinguish hPPAR gamma partial agonists from full agonists. (C) 2015 Elsevier Ltd. All rights reserved.