Endocrine Abstracts (2001) 2 SP21

Structural Basis of Agonism and Antagonism in the Oestrogen Receptor

RE Hubbard1, ACW Pike1, AM Brzozowski1, T Bonn2, M Carlquist2 & JA Gustafsson3

1Dept of Chemistry, University of York, York, UK; 2Karo Bio AB, NOVUM, S-14157 Huddinge, Sweden; 3Departments of Medical Nutrition and Biosciences, Karolinska Institute, NOVUM, S-14186 Huddinge, Sweden.

The oestrogen receptor (ER) is a ligand-inducible transcription factor that controls expression of a number of genes in a wide variety of tissues. Binding of the natural hormone, oestradiol, triggers dimerisation and nuclear location of the receptor and assembly of a functional transcriptional complex through recruitment of various coactivators.

In this talk, I will discuss how knowledge of the structure of the receptor has had a major impact on our understanding of how the receptor works at the molecular level. We have determined the structure of the ligand binding domain of both the alpha and beta forms of ER complexed to different ligands, including partial and full agonists and selective and full antagonists. This has provided insights at the molecular level into some key aspects of the pharmacology and function of this molecule:

- Understanding the distinctive ER pharmacophore

- A rationale for the large range of molecules that bind to ER

- Description of the biologically active dimer

- Structural basis for the action of different antagonists such as raloxifene and ICI 164,384

- Indications of the site of interaction with some co-activators

(see Brzozowski et al, Nature (1997), 389, 753-758, Pike et al (1999), Embo J, 18, 4608-4618, Pike et al (2001), Structure, 9, 145-153).

This presentation will review these structural results and how they relate to the known function of the receptor(s).

The work I will present was funded by Karo Bio and the infrastructure of the Structural Biology Laboratory at York is funded by the BBSRC.

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