Ligand unbinding from the estrogen receptor: a computational study of pathways and ligand specificity.

The estrogen receptor (ER) belongs to the nuclear receptor superfamily, whose members regulate important cellular events like development and metabolism. The ER functions as a transcription regulator and can be activated on ligand binding. Consequently, ligand binding and unbinding constitute fundamental processes in the regulation of genes. Even though both biochemical and structural data of ER are available, the actual mechanism of the ligand binding/unbinding remains elusive. We have performed computational studies on the unbinding mechanism of ERalpha and ERbeta, in the presence of cofactors and with ligands ranging from agonist to a full antagonist. Our results show that agonists or selective ER modulators can dissociate from the receptor through multiple pathways with minor effect on the receptor structure, whereas an antagonist requires larger conformational changes. Furthermore, a specific receptor/ligand combination can exhibit a pathway preference depending on character and conformation of both parts. Hence, it is possible that the binding/unbinding mechanism can explain ligand subtype specificity and thus have an impact in drug discovery. 2009 Wiley-Liss, Inc.