LIGAND-BINDING AND COACTIVATOR ASSEMBLY OF THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA

The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a ligand-dependent transcription factor that is Important in adipocyte differentiation and glucose homeostasis and which depends on Interacti ons with co-activators, including steroid receptor co-activating facto r-1 (SRC-1), Here we present the X-ray crystal structure of the human apo-PPAR-gamma ligand-binding domain (LBD), at 2.2 Angstrom resolution ; this structure reveals a large binding pocket, which may explain the diversity of ligands for PPAR-gamma, We also describe the ternary com plex containing the PPAR-gamma LED, the antidiabetic ligand rosiglitaz one (BRL49653), and 88 amino acids of human SRC-1 at 2.3 Angstrom reso lution. Glutamate and lysine residues that are highly conserved in LBD s of nuclear receptors form a 'charge clamp' that contacts backbone at oms of the LXXLL helices of SRC-1. These results, together with the ob servation that two consecutive LXXLL motifs of SRC-1 make identical co ntacts with both subunits of a PPAR-gamma homodimer, suggest a general mechanism for the assembly of nuclear receptors with co-activators.