A ternary switch model governing ERα ligand binding domain conformation

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.