Crystal structure of the ligand binding domain of the human nuclear receptor PPARγ

The peroxisome proliferator-activated receptors (PPAR) are members of the nuclear receptor supergene family and are considered as key sensors of both lipid and glucose homeostasis, The role of the PPAR gamma isoform in glucose metabolism is illustrated by the fact that antidiabetic thiazolidinediones have been shown to be bona fide PPAR gamma ligands. Here we report the crystal structure of apo-PPAR gamma ligand binding domain (LBD) determined to 2.9-Angstrom resolution. Although the structure of apo-PPAR gamma-LBD retains the overall fold described previously for other nuclear receptor LBDs, three distinct structural differences are evident. 1) The core AF-2 activation domain of apo-PPAR gamma LED is folded back toward the predicted ligand binding pocket similar to that observed in the hole-forms of other nuclear receptors. 2) The proposed ligand binding pocket of apo-PPAR gamma-LBD is larger and more accessible to the surface in contrast to other LBDs. 3) The region of the LED called the omega-loop is extended in PPAR gamma and contains additional structural elements. Taken together, the apo-PPAR gamma-LBD structure is in several aspects different from previously described LBDs, Given the central role of PPAR gamma as a mediator in glucose regulation, the structure should be an important tool in the development of improved anti-diabetic agents.