A Dynamic Structural Model for Estrogen Receptor-α Activation by Ligands, Emphasizing the Role of Interactions between Distant A and E Domains

The functional interplay between different domains of estrogen receptor-α (ERα, NR3A1) is responsible for the overall properties of the full-length protein. We previously identified an interaction between the N-terminal A and C-terminal domains, which we demonstrate here to repress ligand-independent transactivation and transrepression abilities of ERα. Using targeted mutations based on ERα structural models, we determine the basis for this interaction that defines a regulatory interplay between ERα A domain, corepressors, and ERα Helix 12 for binding to the same C-terminal surface. We propose a dynamic model where binding of different ligands influences the A/D-F domain interaction and results in specific functional outcomes. This model gives insights into the dynamic properties of full-length ERα and into the structure of unliganded ERα.