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Molecular basis of agonism and antagonism in the oestrogen receptor

Abstract

Oestrogens are involved in the growth, development and homeostasis of a number of tissues1. The physiological effects of these steroids are mediated by a ligand-inducible nuclear transcription factor, the oestrogen receptor (ER)2. 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 machinery3,4. Here we report the crystal structures of the LBD of ER in complex with the endogenous oestrogen, 17β-oestradiol, and the selective antagonist raloxifene5, 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.

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Figure 1: Ribbon representations of the ER-α LBD.
Figure 2: Agonist and antagonist binding modes.
Figure 3: Positioning of helix H12.

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Author notes

  1. Correspondence and requests for materials should be addressed to R.E.H. Coordinates have been deposited at the Brookhaven Protein DataBank, accession codes 1ERE for the oestradiol-liganded structure and 1ERR for the raloxifene-liganded structure.

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    Correspondence to Roderick E. Hubbard.

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    Brzozowski, A., Pike, A., Dauter, Z. et al. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 389, 753–758 (1997). https://doi.org/10.1038/39645

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