HORMONE-DEPENDENT COACTIVATOR BINDING TO A HYDROPHOBIC CLEFT ON NUCLEAR RECEPTORS

The ligand-binding domain of nuclear receptors contains a transcriptio nal activation function (AF-2) that mediates hormone-dependent binding of coactivator proteins. Scanning surface mutagenesis on the human th yroid hormone receptor was performed to define the site that binds the coactivators, glucocorticoid receptor-interacting protein 1 (GRIP1) a nd steroid receptor coactivator 1 (SRC-1), The residues involved encir cle a small surface that contains a hydrophobic cleft. Ligand activati on of transcription involves formation of this surface by folding the carboxyl-terminal cr helix against a scaffold of three other helices. These features may represent general ones for nuclear receptors.