Estrogen Receptors (ERs) exhibit significant structural flexibility, with conformational adjustments largely influenced by the type of ligand bound and the specific sequence of the Estrogen Response Element (ERE) to which they attach. Research using crystallographic analysis has demonstrated that even a single nucleotide variation in the ERE can lead to significant structural alterations in the DNA Binding Domain (DBD) of the ER. These alterations are facilitated by a rearrangement of side chains within the receptor, which in turn modifies the hydrogen-bonding interactions between the DNA bases and ER amino acids. Consequently, this reorganization affects the ER’s binding interactions with the ERE.
Protease sensitivity assays further support this variability, showing that ER alpha (ERα) adopts distinct conformations when associated with various ERE sequences. These assays use proteases to selectively cleave accessible amino acids within the ERα, revealing structural changes when ERα binds to different EREs across various genes. (e.g., African clawed frog (Xenopus laevis) vitellogenin A2 and B1 genes, human pS2 gene, and gene encoding human oxytocin).
These sequence-dependent conformational changes in ERα impact the recruitment of different co-regulatory proteins to the ER-ERE complex. This recruitment variability leads to differential transcriptional activation across genes. The inherent flexibility and structural adaptability of the Estrogen Receptor (ER) thus play a pivotal role in the diverse range of estrogen signaling pathways.
