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Updated: Aug 18, 2026

Detecting the Ligand-binding Domain Dimerization Activity of Estrogen Receptor Alpha Using the Mammalian Two-Hybrid Assay
09:07

Detecting the Ligand-binding Domain Dimerization Activity of Estrogen Receptor Alpha Using the Mammalian Two-Hybrid Assay

Published on: December 19, 2018

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

Ya-Ling Wu1, Xiaojing Yang, Zhong Ren

  • 1The Ben May Institute for Cancer Research and Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois 60637, USA.

Molecular Cell
|May 17, 2005
PubMed

Insights

A novel compound, GW5638, offers a new way to fight estrogen-dependent breast cancer by destabilizing the estrogen receptor alpha (ERalpha). This mechanism may overcome resistance to tamoxifen treatment.

Area of Science:

  • Molecular Biology
  • Endocrinology
  • Structural Biology

Background:

  • Tamoxifen is a standard treatment for estrogen-dependent breast cancers but can increase endometrial tumor risk.
  • Selective estrogen receptor modulators (SERMs) like tamoxifen target the estrogen receptor (ER).

Purpose of the Study:

  • To elucidate the structural mechanism of GW5638, a tamoxifen-like compound with potential therapeutic benefits and no uterine stimulation.
  • To understand how GW5638 antagonizes the estrogen receptor alpha (ERalpha).

Main Methods:

  • Determined the crystal structure of the ERalpha ligand binding domain (LBD) complexed with GW5638.
  • Analyzed the repositioning of helix H12 and its interaction with GW5638.
  • Assessed the impact of GW5638 on ERalpha stability in MCF-7 cells.

Main Results:

  • GW5638, like tamoxifen, relocates helix H12 in the ERalpha LBD.
  • GW5638 induces specific contacts at the N terminus of H12, altering its position.
  • This repositioning exposes hydrophobic surfaces and significantly destabilizes ERalpha in breast cancer cells.

Conclusions:

  • The GW5638-ERalpha LBD structure reveals a novel SERM antagonism mechanism involving ERalpha destabilization.
  • This dual antagonism mode, distinct from tamoxifen, may explain GW5638's efficacy against tamoxifen-resistant breast tumors.

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