Binding to receptors in the cell nucleus is crucial for the action of lipophilic hormones and ligands. PPAR-γ (for peroxisome proliferator-activated receptor) is a nuclear hormone receptor that mediates adipocyte differentiation, and modulates insulin sensitivity, cell proliferation and inflammatory processes,. PPAR-γ ligands have been implicated in the development of atherogenic foam cells and as potential cancer treatments. Transcriptional activity of PPAR-γ is induced by binding diverse ligands, including natural fatty acid derivatives^,,, antidiabetic thiazolidinediones, and non-steroidal anti-inflammatory drugs. Ligand binding by PPAR-γ, as well as by the entire nuclear-receptor superfamily, is an independent property of the carboxy-terminal ligand-binding domain (LBD) of the receptor,. Here we show that ligand binding by PPAR-γ is regulated by intramolecular communication between its amino-terminal A/B domain and its carboxy-terminal LBD. Modification of the A/B domain, for example by physiological phosphorylation by MAP kinase, reduces ligand-binding affinity, thus negatively regulating the transcriptional and biological functions of PPAR-γ. The ability of the A/B domain to regulate ligand binding has important implications for the evaluation and mechanism of action of potentially therapeutic ligands that bind PPAR-γ and that are likely to extend to other members of the nuclear-receptor superfamily.