Full-length estrogen receptor alpha and its ligand-binding domain adopt different conformations upon binding ligand.

The binding of ligand to a nuclear receptor causes conformational changes that can result in coactivator or corepressor recruitment and subsequent regulation of transcription. Several peptides have previously been identified that bind to the liganded estrogen receptor (ER). One interacting peptide, pepalphaII, was used in the present studies to assess the ability of ligands to induce spatial changes within both the full-length human estrogen receptor alpha (ER-alpha) and a truncated receptor containing the ligand-binding domain (LBD). pepalphaII interacted weakly with the full-length estrogen receptor alpha in the presence of both agonists and antagonists. In contrast, the interaction of pepalphaII with the truncated receptor containing the ligand-binding domain was strongly induced by antagonists and only weakly induced by agonists. Thus, the same ligand can induce different spatial configurations of the full-length and ligand-binding domain of estrogen receptor alpha as measured by pepalphaII affinity. Crystal structures of nuclear hormone receptors solved to date have used ligand-binding domains and therefore may not accurately predict surface interaction domains present in the liganded full-length receptor. Furthermore, the ability of a ligand to induce a strong interaction of pepalphaII with the estrogen receptor alpha ligand-binding domain predicts that the ligand will have greater antagonist activity on the full-length receptor.