Structural differences between the ligand-binding pockets of estrogen receptors alpha and beta

The estrogen receptor (ER) is a member of the nuclear receptor superfamily and has two subtypes: ER alpha and ER beta. Inhibition of ER alpha is an effective therapeutic strategy in breast cancer. In contrast, ER beta is the presumed drug target of various autoimmune diseases. Many experimental structures of ER alpha/beta have been reported; however, their structures vary due to ligand variability. Here, we performed structural bioinformatics studies for three-dimensional structures of ERs retrieved from the protein data bank (PDB) and clarify the detailed structural differences between ER alpha and ER beta. In total, 48 structures registered in the PDB were analyzed by HBOP and HBSITE, which we developed to identify ligand-binding cavities in proteins. PDB entries were clustered by number, shape, size, and location of the ligand-binding pockets. In addition, C-terminal domain shapes, which are divided into "agonist form" and "antagonist form," were also used for clustering. We classified 27 entries of ER alpha into five clusters and 21 entries of ER beta into seven clusters (a total of 12 clusters). Differences in the pockets and hydrogen bonds with ligands were observed between ER alpha and ER beta and occurred even within the same ER species. Therefore, we conclude that the structure of ERs is diverse and is affected by ligands.