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Molecular basis of agonism and antagonism in the oestrogen receptor

Nature volume 389, pages 753–758 (1997)Cite this article

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.

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Figure 1: Ribbon representations of the ER-α LBD.
Figure 2: Agonist and antagonist binding modes.
Figure 3: Positioning of helix H12.

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References

  1. Ciocca, D. R. & Roig, L. M. V. Estrogen-receptors in human nontarget tissues—Biological and clinical implications. Endocr. Rev. 16, 35–62 (1995).

    Google Scholar 

  2. Tsai, M.-J. & O'Malley, B. W. Molecular mechanisms of action of steroid/thyroid receptor superfamily members. Annu. Rev. Biochem. 63, 451–486 (1994).

    Google Scholar 

  3. Katzenellenbogen, J. A., O'Malley, B. W. & Katzenellenbogen, B. S. Tripartite steroid hormone receptor pharmacology: Interaction with multiple effector sites as a basis for the cell- and promoter-specific action of these hormones. Mol. Endocrinol. 10, 119–131 (1996).

    Google Scholar 

  4. Beato, M. & Sánchez-Pacheco, A. Interaction of steroid hormone receptors with the transcription initiation complex. Endocr. Rev. 17, 587–609 (1996).

    Google Scholar 

  5. Grese, T. A. et al. Structure-activity relationships of selective estrogen receptor modulators: Modifications to the 2-arylbenzothiophene core of raloxifene. J. Med. Chem. 40, 146–167 (1997).

    Google Scholar 

  6. Wagner, R. L. et al. Astructural role for hormone in the thyroid hormone receptor. Nature 378, 690–697 (1995).

    Article  ADS  CAS  Google Scholar 

  7. Renaud, J.-P. et al. Crystal structure of the RAR-γ ligand-binding domain bound to all- trans retinoic acid. Nature 378, 681–689 (1995).

    Article  ADS  CAS  Google Scholar 

  8. Bourguet, W., Ruff, M., Chambon, P., Gronemeyer, H. & Moras, D. Crystal structure of the ligand-binding domain of the human nuclear receptor RXR-α. Nature 375, 377–382 (1995).

    Article  ADS  CAS  Google Scholar 

  9. Wurtz, J.-M. et al. Acanonical structure for the ligand-binding domain of nuclear receptors. Nature Struct. Biol. 3, 87–94 (1996).

    Google Scholar 

  10. Kumar, V. & Chambon, P. The estrogen receptor binds tightly to its responsive element as a ligand-induced homodimer. Cell 55, 145–156 (1988).

    Google Scholar 

  11. Fawell, S. E., Lees, J. A., White, R. & Parker, M. G. Characterisation and colocalization of steroid binding and dimerization activities in the mouse estrogen receptor. Cell 60, 953–962 (1990).

    Google Scholar 

  12. Anstead, G. M., Carlson, K. E. & Katzenellenbogen, J. A. The estradiol pharmacophore: Ligand structure–estrogen receptor binding affinity relationships and a model for the receptor binding site. Steroids 62, 268–303 (1997).

    Google Scholar 

  13. Katzellenbogen, B. S. et al. Antiestrogens: Mechanisms and actions in target cells. J. Steroid Biochem. Mol. Biol. 53, 387–393 (1995).

    Google Scholar 

  14. Draper, M. W. et al. Acontrolled trial of raloxifene (LY139481) HCl: Impact on bone turnover and serum lipid profile in healthy postmenopausal women. J. Bone Miner. Res. 11, 835–842 (1996).

    Google Scholar 

  15. Ekena, K., Weis, K. E., Katzenellenbogen, J. A. & Katzenellenbogen, B. S. Different residues of the human estrogen receptor are involved in the recognition of structurally diverse estrogens and antiestrogens. J. Biol. Chem. 272, 5069–5075 (1997).

    Google Scholar 

  16. Cavaillès, V., Dauvois, S., Danielian, P. S. & Parker, M. G. Interaction of proteins with transcriptionally active estrogen receptors. Proc. Natl Acad. Sci. USA 91, 10009–10013 (1994).

    Google Scholar 

  17. L'Horset, F., Dauvois, S., Heery, D. M., Cavaillès, V. & Parker, M. G. RIP-140 interacts with multiple nuclear receptors by means of two distinct sites. Mol. Cell. Biol. 16, 6029–6036 (1996).

    Google Scholar 

  18. vom Baur, E. et al. Differential ligand-dependent interactions between the AF-2 activating domain of nuclear receptors and the putative transcriptional intermediary factors mSUG1 and TIF1. EMBO J. 15, 110–124 (1996).

    Google Scholar 

  19. Danielian, P. S., White, R., Lees, J. A. & Parker, M. G. Identification of a conserved region required for hormone dependent transcriptional activation by steroid hormone receptors. EMBO J. 11, 1025–1033 (1992).

    Google Scholar 

  20. Pakdel, F., Reese, J. C. & Katzenellenbogen, B. S. Identification of charged residues in an N-terminal portion of the hormone-binding domain of the human estrogen receptor important in transcriptional activity of the receptor. Mol. Endocrinol. 7, 1408–1417 (1993).

    Google Scholar 

  21. Henttu, P. M. A., Kalkhoven, E. & Parker, M. G. AF-2 activity and recruitment of steroid receptor coactivator 1 to the estrogen receptor depend on a lysine residue conserved in nuclear receptors. Mol. Cell. Biol. 17, 1832–1839 (1997).

    Google Scholar 

  22. McInerney, E. M. & Katzenellenbogen, B. S. Different regions in activation function-1 of the human estrogen receptor required for antiestrogen- and estradiol-dependent transcriptional activation. J.Biol. Chem. 271, 24172–24178 (1996).

    Google Scholar 

  23. McInerney, E. M., Tsai, M.-J., O'Malley, B. W. & Katzenellenbogen, B. S. Analysis of estrogen receptor transcriptional enhancement by a nuclear hormone receptor coactivator. Proc. Natl Acad. Sci. USA 93, 10069–10073 (1996).

    Google Scholar 

  24. Hegy, G. B. et al. Carboxymethylation of the human estrogen receptor ligand-binding domain-estradiol complex: HPLC/ESMS peptide mapping shows that cysteine 447 does not react with iodoacetic acid. Steroids 61, 367–373 (1996).

    Google Scholar 

  25. Otwinowski, Z. & Minor, W. Processing X-ray diffraction data collected in oscillation mode. Methods Enzymol. 276, 307–326 (1997).

    Google Scholar 

  26. Collaborative Computational Project No. 4. The CCP4 suite: programs for protein crystallography. Acta Crystallogr. D 50, 760–763 (1994).

  27. Murshudov, G. N., Vagin, A. A. & Dodson, E. J. Refinement of macromolecular structures by the maximum-likelihood method. Acta Crystallogr. D 53, 240–255 (1997).

    Google Scholar 

  28. Wallace, A. C., Laskowski, R. A. & Thornton, J. M. LIGPLOT—A program to generate schematic diagrams of protein ligand interactions. Prot. Eng. 8, 127–134 (1995).

    Google Scholar 

  29. Laskowski, R. A., MacArthur, M. W., Moss, D. S. & Thornton, J. M. PROCHECK: a programme to check the stereochemical quality of protein structure coordinates. J. Appl. Crystallogr. A 42, 140–149 (1993).

    Google Scholar 

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Author notes

  1. Andrzej M. Brzozowski and Ashley C. W. Pike: These authors contributed equally to this work.

Authors and Affiliations

  1. Chemistry Department, Protein Structure Group, University of York, York, YO15DD, UK

    Andrzej M. Brzozowski, Ashley C. W. Pike, Zbigniew Dauter & Roderick E. Hubbard

  2. Karo Bio AB, NOVUM, S-141 57, Huddinge, Sweden

    Tomas Bonn, Owe Engström, Lars Öhman & Mats Carlquist

  3. The Ben May Institute for Cancer Research, The University of Chicago, 5841 S. Maryland Ave, Chicago, 60637, Illinois, USA

    Geoffrey L. Greene

  4. Karolinska Institute, S-141 86, Huddinge, Sweden

    Jan-Åke Gustafsson

Author notes

  1. Correspondence and requests for materials should be addressed to R.E.H. Coordinates have been deposited at the Brookhaven Protein DataBank, accession codes 1ERE for the oestradiol-liganded structure and 1ERR for the raloxifene-liganded structure.

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    1. Andrzej M. Brzozowski
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    Correspondence to Roderick E. Hubbard.

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    Brzozowski, A., Pike, A., Dauter, Z. et al. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 389, 753–758 (1997). https://doi.org/10.1038/39645

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