MOLECULAR-BASIS OF AGONISM AND ANTAGONISM IN THE ESTROGEN-RECEPTOR

Oestrogens are involved in the growth, development and homeostasis of a number of tissues(1). The physiological effects of these steroids ar e mediated by a ligand-inducible nuclear transcription factor, the oes trogen receptor (ER)(2). Hormone binding to the ligand-binding domain (LED) of the ER initiates a series of molecular events culminating in the activation or repression of target genes, Transcriptional regulati on arises from the direct interaction of the ER with components of the cellular transcription machinery(3,4). Here we report the crystal str uctures of the LED of ER in complex with the endogenous oestrogen, 17 beta-oestradiol, and the selective antagonist raloxifene(5), at resolu tions of 3.1 and 2.6 Angstrom, respectively. The structures provide a molecular basis for the distinctive pharmacophore of the ER and its ca tholic binding properties, Agonist and antagonist bind at the same sit e within the core of the LED but demonstrate different binding modes, In addition, each class of ligand induces a distinct conformation in t he transactivation domain of the LED, providing structural evidence of the mechanism of antagonism.