Structural characterization of a subtype-selective ligand reveals a novel mode of estrogen receptor antagonism

Andrew K. Shiau, Danielle Barstad, James T. Radek, Marvin J. Meyers, Kendall W. Nettles, Benita S. Katzenellenbogen, John A. Katzenellenbogen, David A. Agard, Geoffrey L. Greene

Research output: Contribution to journalArticle

Abstract

The R,R enantiomer of 5,11-cis-diethyl-5,6,11,12-tetrahydrochrysene-2,8-diol (THC) exerts opposite effects on the transcriptional activity of the two estrogen receptor (ER) subtypes, ERα and ERβ. THC acts as an ERα agonist and as an ERβ antagonist. We have determined the crystal structures of the ERα ligand binding domain (LBD) bound to both THC and a fragment of the transcriptional coactivator GRIP1, and the ERβ LBD bound to THC. THC stabilizes a conformation of the ERα LBD that permits coactivator association and a conformation of the ERβ LBD that prevents coactivator association. A comparison of the two structures, taken together with functional data, reveals that THC does not act on ERβ through the same mechanisms used by other known ER antagonists. Instead, THC antagonizes ERβ through a novel mechanism we term 'passive antagonism'.

Original languageEnglish (US)
Pages (from-to)359-364
Number of pages6
JournalNature Structural Biology
Volume9
Issue number5
DOIs
StatePublished - May 13 2002

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Genetics

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    Shiau, A. K., Barstad, D., Radek, J. T., Meyers, M. J., Nettles, K. W., Katzenellenbogen, B. S., Katzenellenbogen, J. A., Agard, D. A., & Greene, G. L. (2002). Structural characterization of a subtype-selective ligand reveals a novel mode of estrogen receptor antagonism. Nature Structural Biology, 9(5), 359-364. https://doi.org/10.1038/nsb787