| Nuclear receptors, members of a superfamily of eukaryotic transcription factors, regulate gene expression in response to small, hydrophobic ligands. The receptors exhibit a modular structure. with functionally separable domains. One of the most highly-conserved domains is the ligand-binding domain (LBD). The ligand binding domain adopts distinct conformations as apo-receptors, agonist-bound or antagonist-bound species, which support or preclude interactions with proteins such as transcriptional corepressors and transcriptional coactivators.; To understand how hormone exerts its control over the activity of the nuclear receptors, we determined the crystal structure of the liganded thyroid hormone receptor LBD, alone and in complex with a peptide from GRIP-1, a p160 coactivator. In these structures, the ligand is completely buried within the domain as pall of the hydrophobic core. The conserved leucine residues of the p160 coactivator bind a highly conserved hydrophobic cleft formed by helices H3, H4, H5, and H12 of the TR LBD, defining the activation function AF-2 within the LBD. Similarity between the NR-box peptide in the cocrystal, and alpha-helix H12 in the structure of the raloxifene-bound estrogen receptor (ER) LBD, suggests the antagonist-bound LBD fails to interact with p160 coactivators by eliminating the part of the coactivator interaction surface that involves H12, and occluding the remaining part of the coactivator interaction surface. These observations suggest a structural role for hormone, in establishing the active conformation of the receptor, that is likely to underlie hormonal regulation of gene expression for the nuclear receptors. |
