Article abstract

Nature Chemical Biology 4, 241 - 247 (2008)
Published online: 16 March 2008 | Corrected online: 1 May 2008 | doi:10.1038/nchembio.76

NFkappaB selectivity of estrogen receptor ligands revealed by comparative crystallographic analyses

Kendall W Nettles1,8, John B Bruning1,8, German Gil1, Jason Nowak1, Sanjay K Sharma2, Johnnie B Hahm2, Kristen Kulp3, Richard B Hochberg4, Haibing Zhou5, John A Katzenellenbogen5, Benita S Katzenellenbogen6, Younchang Kim7, Andrzej Joachimiak7 & Geoffrey L Greene2

Our understanding of how steroid hormones regulate physiological functions has been significantly advanced by structural biology approaches. However, progress has been hampered by misfolding of the ligand binding domains in heterologous expression systems and by conformational flexibility that interferes with crystallization. Here, we show that protein folding problems that are common to steroid hormone receptors are circumvented by mutations that stabilize well-characterized conformations of the receptor. We use this approach to present the structure of an apo steroid receptor that reveals a ligand-accessible channel allowing soaking of preformed crystals. Furthermore, crystallization of different pharmacological classes of compounds allowed us to define the structural basis of NFkappaB-selective signaling through the estrogen receptor, thus revealing a unique conformation of the receptor that allows selective suppression of inflammatory gene expression. The ability to crystallize many receptor-ligand complexes with distinct pharmacophores allows one to define structural features of signaling specificity that would not be apparent in a single structure.

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  1. Department of Cancer Biology, The Scripps Research Institute, 5353 Parkside Drive, Jupiter, Florida 33458, USA.
  2. Ben May Department for Cancer Research, University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.
  3. Biosciences and Biotechnology Division, Chemistry Materials and Life Sciences Directorate, Lawrence Livermore National Laboratory, 7000 East Avenue L-452, Livermore, California 94550, USA.
  4. Department of Obstetrics/Gynecology and Reproductive Sciences, and the Comprehensive Cancer Center, Yale University School of Medicine, 310 Cedar Street, New Haven, Connecticut 06520, USA.
  5. Department of Chemistry, 600 South Mathews Avenue, Urbana, Illinois 61801, USA.
  6. Departments of Molecular and Integrative Physiology, Cell and Developmental Biology, University of Illinois, 600 South Mathews Avenue, Urbana, Illinois 61801, USA.
  7. Midwest Center for Structural Genomics and Structural Biology Center, Argonne National Laboratory, 9700 South Cass Avenue, Argonne, Illinois 60439, USA.
  8. These authors contributed equally to this work.

Correspondence to: Kendall W Nettles1,8 e-mail: knettles@scripps.edu

Correspondence to: Geoffrey L Greene2 e-mail: ggreene@uchicago.edu

* In the version of this article initially published, the 13th author's last name is misspelled. The author's name should read 'Andrzej Joachimiak'. Additionally, Figure 5 of this article inadvertently contains pink traces in each panel that are not attributed to any specific molecule. These errors have been corrected in the HTML and PDF versions of the article.