Peroxisome proliferator-activated receptor gamma (PPAR gamma) has multiple binding points that accommodate ligands in various conformations: Structurally similar PPAR gamma partial agonists bind to PPAR gamma LBD in different conformations

摘要

In the course of studies directed toward the creation of human peroxisome proliferator-activated receptor gamma (hPPAR gamma) partial agonists, we designed and synthesized benzylsulfonylaminocarbonyl derivative (3) by structural modification of our reported hPPAR gamma partial agonist 2. Co-crystallization of 3 with the hPPAR gamma ligand-binding domain (LBD) afforded a homodimeric complex in which one of the LBDs adopts a fully active structure without bound 3, while the other LBD exhibits a non-fully active structure containing one molecule of bound 3. Interestingly, 2 and 3 are structurally similar, but bind to hPPAR gamma LBD in distinct conformations, that is, the sulfonylaminocarbonyl moiety of bound 3 is directed at 180 degrees away from that of bound 2. These results support our previous proposal that the hPPAR gamma LBD has multiple binding points that can be utilized to accommodate structurally flexible hPPAR ligands. (C) 2015 Elsevier Ltd. All rights reserved.