Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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

Nature Structural Biology volume 9, pages 359–364 (2002)Cite this article

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'.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Overall structures of the THC–ER LBD complexes.
Figure 2: Conformational equilibrium of helix 12.
Figure 3: THC–ligand-binding pocket interactions.
Figure 4: Ligand-binding pocket residues influence helix 12 positioning.

Similar content being viewed by others

Accession codes

Accessions

Protein Data Bank

References

  1. Katzenellenbogen, B.S. & Katzenellenbogen, J.A. Breast Cancer Res. 2, 335–344 (2000).

    Article  CAS  Google Scholar 

  2. Pettersson, K. & Gustafsson, J.A. Annu. Rev. Physiol. 63, 165–192 (2001).

    Article  CAS  Google Scholar 

  3. Meyers, M.J., Sun, J., Carlson, K.E., Katzenellenbogen, B.S. & Katzenellenbogen, J.A. J. Med. Chem. 42, 2456–2468 (1999).

    Article  CAS  Google Scholar 

  4. Sun, J. et al. Endocrinology 140, 800–804 (1999).

    Article  CAS  Google Scholar 

  5. Kraichely, D.M., Sun, J., Katzenellenbogen, J.A. & Katzenellenbogen, B.S. Endocrinology 141, 3534–3545 (2000).

    Article  CAS  Google Scholar 

  6. Pham, T.A., Hwung, Y.P., Santiso-Mere, D., McDonnell, D.P. & O'Malley, B.W. Mol. Endocrinol. 6, 1043–1050 (1992).

    CAS  PubMed  Google Scholar 

  7. Tzukerman, M.T. et al. Mol. Endocrinol. 8, 21–30 (1994).

    CAS  PubMed  Google Scholar 

  8. McInerney, E.M., Weis, K.E., Sun, J., Mosselman, S. & Katzenellenbogen, B.S. Endocrinology 139, 4513–4522 (1998).

    Article  CAS  Google Scholar 

  9. Barkhem, T. et al. Mol. Pharmacol. 54, 105–112 (1998).

    Article  CAS  Google Scholar 

  10. Danielian, P.S., White, R., Lees, J.A. & Parker, M.G. EMBO J. 11, 1025–1033 (1992).

    Article  CAS  Google Scholar 

  11. Berry, M., Metzger, D. & Chambon, P. EMBO J. 9, 2811–2818 (1990).

    Article  CAS  Google Scholar 

  12. Kraus, W.L., McInerney, E.M. & Katzenellenbogen, B.S. Proc. Natl. Acad. Sci. USA 92, 12314–12318 (1995).

    Article  CAS  Google Scholar 

  13. Steinmetz, A.C., Renaud, J.P. & Moras, D. Annu. Rev. Biophys. Biomol. Struct. 30, 329–359 (2001).

    Article  CAS  Google Scholar 

  14. Weatherman, R.V., Fletterick, R.J. & Scanlan, T.S. Annu. Rev. Biochem. 68, 559–581 (1999).

    Article  CAS  Google Scholar 

  15. Glass, C.K. & Rosenfeld, M.G. Genes Dev. 14, 121–141 (2000).

    CAS  PubMed  Google Scholar 

  16. Bourguet, W. et al. Mol. Cell 5, 289–298 (2000).

    Article  CAS  Google Scholar 

  17. Shiau, A.K. et al. Cell 95, 927–937 (1998).

    Article  CAS  Google Scholar 

  18. Brzozowski, A. et al. Nature 389, 753–758 (1997).

    Article  CAS  Google Scholar 

  19. Pike, A.C. et al. EMBO J. 18, 4608–4618 (1999).

    Article  CAS  Google Scholar 

  20. Pike, A.C. et al. Structure 9, 145–153 (2001).

    Article  CAS  Google Scholar 

  21. Shiau, A.K., Coward, P., Schwarz, M. & Lehmann, J.M. Curr. Opin. Drug Discov. Devel. 4, 575–590 (2001).

    CAS  PubMed  Google Scholar 

  22. Singh, S.M., Gauthier, S. & Labrie, F. Curr. Med. Chem. 7, 211–247 (2000).

    Article  CAS  Google Scholar 

  23. Souque, A. et al. Endocrinology 136, 5651–5658 (1995).

    Article  CAS  Google Scholar 

  24. Mangelsdorf, D.J. et al. Cell 83, 835–839 (1995).

    Article  CAS  Google Scholar 

  25. Otwinowski, Z. & Minor, W. Methods Enzymol. 276, 307–326 (1997).

    Article  CAS  Google Scholar 

  26. Dodson, E.J., Winn, M. & Ralph, A. Methods Enzymol. 277, 620–634 (1997).

    Article  CAS  Google Scholar 

  27. Muller, K. et al. Bull. Soc. Chim. Belge. 97, 655–667 (1988).

    Article  Google Scholar 

  28. Kleywegt, G.J. & Jones, T.A. Acta Crystallogr. D 55, 941–944. (1999).

    Article  CAS  Google Scholar 

  29. Furey, W. & Swaminathan, S. Methods Enzymol. 277, 590–619 (1997).

    Article  CAS  Google Scholar 

  30. Brünger, A.T. et al. Acta Crystallogr. D 54, 905–921 (1998).

    Article  Google Scholar 

  31. Stehle, T., Gamblin, S.J., Yan, Y. & Harrison, S.C. Structure 4 165–182 (1996).

    Article  CAS  Google Scholar 

  32. Esnouf, R.M. J. Mol. Graph. Model. 15, 132–134, 112–113 (1997).

    Article  CAS  Google Scholar 

  33. Merritt, E.A. & Bacon, D.J. Methods Enzymol. 277, 505–524 (1997).

    Article  CAS  Google Scholar 

  34. Kleywegt, G.J. & Jones, T.A. Methods Enzymol. 277, 525–545 (1997).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank T. Earnest for advice and assistance at beamline 5.0.2 (ALS is funded by the US Department of Energy Office of Basic Energy Sciences). We also thank M. Butte, N. Ota and Y. Shibata for assistance with data collection; P. Coward, A. Derman, and Y. Li for comments on the manuscript; and H. Deacon for extensive graphical assistance. This work was supported by the NIH (B.S.K, J.A.K. and D.A.A), the Howard Hughes Medical Institute (D.A.A.), the Susan G. Komen Breast Cancer Foundation (G.L.G.), the USAMRMC (G.L.G.) and the Illinois Department of Public Health (G.L.G). In the initial phases of this work, A.K.S. was supported by a Howard Hughes Medical Institute Predoctoral Fellowship and a UCSF Chancellor's Fellowship. All crystallographic studies were completed while A.K.S. was at UCSF, and the peptide binding studies were performed by A.K.S. at Tularik Inc.

Author information

Authors and Affiliations

  1. The Howard Hughes Medical Institute and Department of Biochemistry and Biophysics, University of California, San Francisco, 94143, California, USA

    Andrew K. Shiau & David A. Agard

  2. Tularik Inc., Two Corporate Drive, South San Francisco, 94080, California, USA

    Andrew K. Shiau

  3. The Ben May Institute for Cancer Research and Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, 60637, Illinois, USA

    Danielle Barstad, James T. Radek, Kendall W. Nettles & Geoffrey L. Greene

  4. Department of Chemistry, University of Illinois, Urbana, 61801, Illinois, USA

    Marvin J. Meyers & John A. Katzenellenbogen

  5. Departments of Molecular and Integrative Physiology and Cell and Structural Biology, University of Illinois, Urbana, 61801, Illinois, USA

    Benita S. Katzenellenbogen

Authors
  1. Andrew K. Shiau
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Danielle Barstad
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. James T. Radek
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marvin J. Meyers
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kendall W. Nettles
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Benita S. Katzenellenbogen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. John A. Katzenellenbogen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. David A. Agard
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Geoffrey L. Greene
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Andrew K. Shiau or Geoffrey L. Greene.

Ethics declarations

Competing interests

With the exception of A.K.S., all of the authors declare that they have no competing financial interests. A.K.S. declares that he is an employee of a commercial biopharmaceutical company that carries out research in the nuclear receptor field and that, as part of his employment, he receives options to purchase company stock.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shiau, A., Barstad, D., Radek, J. et al. Structural characterization of a subtype-selective ligand reveals a novel mode of estrogen receptor antagonism. Nat Struct Mol Biol 9, 359–364 (2002). https://doi.org/10.1038/nsb787

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nsb787

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing