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Cooperative Allosteric Transitions01:58

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Related Experiment Video

Updated: Jan 10, 2026

Detecting the Ligand-binding Domain Dimerization Activity of Estrogen Receptor Alpha Using the Mammalian Two-Hybrid Assay
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A ternary switch model governing ERα ligand binding domain conformation.

Daniel P McDougal1, Jordan L Pederick1, Scott J Novick2

  • 1Institute for Photonics and Advanced Sensing (IPAS), School of Biological Sciences, The University of Adelaide, Adelaide, SA, Australia.

Nature Communications
|November 24, 2025
PubMed
Summary

Estrogen receptor alpha

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Area of Science:

  • Endocrinology and Molecular Biology
  • Structural Biology
  • Cancer Research

Background:

  • Estrogen receptor alpha (ERα) drives ER+ breast cancer and is a target for cancer drugs.
  • ERα activity depends on helix-12 conformation in the ligand-binding domain.
  • The transition of helix-12 between states remains unclear.

Purpose of the Study:

  • To elucidate the structural basis of ERα helix-12 conformational changes.
  • To investigate the role of apo helix-12 conformation in receptor regulation.
  • To understand how breast cancer mutations affect ERα structure and function.

Main Methods:

  • X-ray crystallography of apo ERα ligand-binding domain.
  • Structural mass spectrometry.
  • Molecular dynamics simulations.

Main Results:

  • A novel, stable apo helix-12 conformation was identified.
  • Ligand binding and conserved residues (L525, L536, L540) displace helix-12.
  • Breast cancer mutations Y537S and D538G disrupt apo helix-12 stabilization.

Conclusions:

  • Helix-12 acts as a ternary molecular switch regulating ERα activity.
  • Findings offer insights into ERα regulation and therapeutic strategies.
  • Understanding ERα conformational dynamics is key for targeted cancer therapies.