additional citation details.......
Published online: 15 April 2002, DOI:10.1038/nsb787
Nature Structural Biology
May 2002 Volume 9 Number 5 pp 359 - 364
Structural characterization of a subtype-selective ligand reveals a novel mode of estrogen receptor antagonism
Andrew K. Shiau1, 2, Danielle Barstad3, James T. Radek3, Marvin J. Meyers4, Kendall W. Nettles3, Benita S. Katzenellenbogen5, John A. Katzenellenbogen4, David A. Agard1 & Geoffrey L. Greene3
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, ER and ER. THC acts as an ER agonist and as an ER antagonist. We have determined the crystal structures of the ER ligand binding domain (LBD) bound to both THC and a fragment of the transcriptional coactivator GRIP1, and the ER LBD bound to THC. THC stabilizes a conformation of the ER LBD that permits coactivator association and a conformation of the ER LBD that prevents coactivator association. A comparison of the two structures, taken together with functional data, reveals that THC does not act on ER through the same mechanisms used by other known ER antagonists. Instead, THC antagonizes ER through a novel mechanism we term 'passive antagonism'.
1. The Howard Hughes Medical Institute and Department of Biochemistry and Biophysics, University of California, San Francisco, California 94143, USA.
2. Tularik Inc., Two Corporate Drive, South San Francisco, California 94080, USA.
3. The Ben May Institute for Cancer Research and Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois 60637, USA.
4. Department of Chemistry, University of Illinois, Urbana, Illinois 61801, USA.
5. Departments of Molecular and Integrative Physiology and Cell and Structural Biology, University of Illinois, Urbana, Illinois 61801, USA
Correspondence should be addressed to A K Shiau. e-mail: ashiau@tularik.com and G L Greene. e-mail: ggreene@uchicago.edu |
