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

Bioorg Med Chem Lett. 2015 Jul 15;25(14):2758-62. doi: 10.1016/j.bmcl.2015.05.025. Epub 2015 May 22.


In the course of studies directed toward the creation of human peroxisome proliferator-activated receptor gamma (hPPARγ) partial agonists, we designed and synthesized benzylsulfonylaminocarbonyl derivative (3) by structural modification of our reported hPPARγ partial agonist 2. Co-crystallization of 3 with the hPPARγ 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 hPPARγ LBD in distinct conformations, that is, the sulfonylaminocarbonyl moiety of bound 3 is directed at 180° away from that of bound 2. These results support our previous proposal that the hPPARγ LBD has multiple binding points that can be utilized to accommodate structurally flexible hPPAR ligands.

Keywords: PPAR; Partial agonist; Peroxisome proliferator-activated receptor; X-ray.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Crystallography, X-Ray
  • Dimerization
  • Humans
  • Ligands*
  • Molecular Dynamics Simulation
  • PPAR gamma / agonists*
  • PPAR gamma / metabolism
  • Pioglitazone
  • Protein Binding
  • Protein Structure, Tertiary
  • Thiazolidinediones / chemistry
  • Thiazolidinediones / metabolism


  • Ligands
  • PPAR gamma
  • Thiazolidinediones
  • Pioglitazone