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Structural basis for an unexpected mode of SERM-mediated ER antagonism.

Publication ,  Journal Article
Wu, Y-L; Yang, X; Ren, Z; McDonnell, DP; Norris, JD; Willson, TM; Greene, GL
Published in: Mol Cell
May 13, 2005
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Tamoxifen is effective for the prevention and treatment of estrogen-dependent breast cancers, but is associated with an increased incidence of endometrial tumors. We report the crystal structure of the estrogen receptor alpha (ERalpha) ligand binding domain (LBD) bound to the structurally similar compound GW5638, which has therapeutic potential and does not stimulate the uterus. Like tamoxifen, GW5638 relocates the carboxy-terminal helix (H12) to the known coactivator-docking site in the ERalpha LBD. However, GW5638 repositions residues in H12 through specific contacts with the N terminus of this helix. In contrast to tamoxifen, the resulting increase in exposed hydrophobic surface of ERalpha LBD correlates with a significant destabilization of ERalpha in MCF-7 cells. Thus, the GW5638-ERalpha LBD structure reveals an unexpected mode of SERM-mediated ER antagonism, in which the stability of ERalpha is decreased through an altered position of H12. This dual mechanism of antagonism may explain why GW5638 can inhibit tamoxifen-resistant breast tumors.

Duke Scholars

Donald Patrick McDonnell
Author Donald Patrick McDonnell Pharmacology & Cancer Biology
John David Norris
Author John David Norris Pharmacology & Cancer Biology
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Published In

Mol Cell

DOI

10.1016/j.molcel.2005.04.014

ISSN

1097-2765

Publication Date

May 13, 2005

Volume

18

Issue

4

Start / End Page

413 / 424

Location

United States

Related Subject Headings

  • Structure-Activity Relationship
  • Stilbenes
  • Selective Estrogen Receptor Modulators
  • Protein Structure, Tertiary
  • Molecular Sequence Data
  • Ligands
  • Hydrophobic and Hydrophilic Interactions
  • Humans
  • Estrogen Receptor alpha
  • Developmental Biology
 

Citation

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MLA
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Wu, Y.-L., Yang, X., Ren, Z., McDonnell, D. P., Norris, J. D., Willson, T. M., & Greene, G. L. (2005). Structural basis for an unexpected mode of SERM-mediated ER antagonism. Mol Cell, 18(4), 413–424. https://doi.org/10.1016/j.molcel.2005.04.014
Wu, Ya-Ling, Xiaojing Yang, Zhong Ren, Donald P. McDonnell, John D. Norris, Timothy M. Willson, and Geoffrey L. Greene. “Structural basis for an unexpected mode of SERM-mediated ER antagonism.” Mol Cell 18, no. 4 (May 13, 2005): 413–24. https://doi.org/10.1016/j.molcel.2005.04.014.
Wu Y-L, Yang X, Ren Z, McDonnell DP, Norris JD, Willson TM, et al. Structural basis for an unexpected mode of SERM-mediated ER antagonism. Mol Cell. 2005 May 13;18(4):413–24.
Wu, Ya-Ling, et al. “Structural basis for an unexpected mode of SERM-mediated ER antagonism.” Mol Cell, vol. 18, no. 4, May 2005, pp. 413–24. Pubmed, doi:10.1016/j.molcel.2005.04.014.
Wu Y-L, Yang X, Ren Z, McDonnell DP, Norris JD, Willson TM, Greene GL. Structural basis for an unexpected mode of SERM-mediated ER antagonism. Mol Cell. 2005 May 13;18(4):413–424.
Journal cover image

Published In

Mol Cell

DOI

10.1016/j.molcel.2005.04.014

ISSN

1097-2765

Publication Date

May 13, 2005

Volume

18

Issue

4

Start / End Page

413 / 424

Location

United States

Related Subject Headings

  • Structure-Activity Relationship
  • Stilbenes
  • Selective Estrogen Receptor Modulators
  • Protein Structure, Tertiary
  • Molecular Sequence Data
  • Ligands
  • Hydrophobic and Hydrophilic Interactions
  • Humans
  • Estrogen Receptor alpha
  • Developmental Biology