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-Åke Gustafsson and Mats Carlquist
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Andrzej M. Brzozowski: Protein Structure Group, University of York
Ashley C. W. Pike: Protein Structure Group, University of York
Zbigniew Dauter: Protein Structure Group, University of York
Roderick E. Hubbard: Protein Structure Group, University of York
Tomas Bonn: Karo Bio AB, NOVUM
Owe Engström: Karo Bio AB, NOVUM
Lars Öhman: Karo Bio AB, NOVUM
Geoffrey L. Greene: The Ben May Institute for Cancer Research, The University of Chicago
Jan-Åke Gustafsson: Karolinska Institute
Mats Carlquist: Karo Bio AB, NOVUM

Nature, 1997, vol. 389, issue 6652, 753-758

Abstract: 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.

Date: 1997
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DOI: 10.1038/39645

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