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 Interactions with co-activators, including steroid receptor co-activating factor-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 complex containing the PPAR-gamma LED, the antidiabetic ligand rosiglitazone (BRL49653), and 88 amino acids of human SRC-1 at 2.3 Angstrom resolution. Glutamate and lysine residues that are highly conserved in LBDs of nuclear receptors form a ＇charge clamp＇ that contacts backbone atoms of the LXXLL helices of SRC-1. These results, together with the observation that two consecutive LXXLL motifs of SRC-1 make identical contacts with both subunits of a PPAR-gamma homodimer, suggest a general mechanism for the assembly of nuclear receptors with co-activators.