Dynamic stabilization of nuclear receptor ligand binding domains by hormone or corepressor binding

We have developed a novel assembly assay to examine structural changes in t he ligand binding domain (LBD) of the thyroid hormone receptor (TR). Fragme nts including the first helix of the TR LED interact only weakly with the r emainder of the LED in the absence of hormone, but this interaction is stro ngly enhanced by the addition of either hormone or the corepressor NCoR. Si nce neither the ligand nor the corepressor shows direct interaction with th is helix, we propose that both exert their effects by stabilizing the overa ll structure of the LED. Current models of activation of nuclear hormone re ceptors focus on a ligand-induced allosteric shift in the position of the C -terminal helix 12 that generates the coactivator binding site. Our results suggest that ligand binding also has more global effects that dynamically alter the structure of the receptor LED.