Molecular basis of agonism and antagonism in the oestrogen receptor

Andrzej M. Brzozowski, Ashley C.W. Pike, Zbigniew Dauter, Roderick E. Hubbard, Tomas Bonn, Owe Engström, Lars Öhman, Geoffrey L. Greene, Jan-Ake Gustafsson, Mats Carlquist

Research output: Contribution to journalArticle

2763 Scopus citations

Abstract

Oestrogens are involved in the growth, development and homeostasis of a number of tissues. The physiological effects of these steroids are mediated by a ligand-inducible nuclear transcription factor, the oestrogen receptor (ER). Hormone binding to the ligand-binding domain (LBD) of the ER initiates a series of molecular events culminating in the activation or repression of target genes. Transcriptional regulation arises from the direct interaction of the ER with components of the cellular transcription machinery. Here we report the crystal structures of the LBD of ER in complex with the endogenous oestrogen, 17β-oestradiol, and the selective antagonist raloxifene, at resolutions of 3.1 and 2.6 Å, respectively. The structures provide a molecular basis for the distinctive pharmacophore of the ER and its catholic binding properties. Agonist and antagonist bind at the same site within the core of the LBD but demonstrate different binding modes. In addition, each class of ligand induces a distinct conformation in the transactivation domain of the LBD, providing structural evidence of the mechanism of antagonism.

Original languageEnglish (US)
Pages (from-to)753-758
Number of pages6
JournalNature
Volume389
Issue number6652
DOIs
StatePublished - Nov 5 1997

ASJC Scopus subject areas

  • General

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