Ligand Specific Estrogen Receptor alpha Conformational Dynamics

Estrogen receptor alpha is overexpressed in 70 percent of breast cancers. Normally, ER-alpha remains inactive and sequestered in the cytoplasm until estrogen binds to the ligand-binding domain (LBD) to enable nuclear translocation, coregulator recruitment, and subsequent activation of proliferative ER-alpha-dependent transcriptomic profiles. Current treatment of ER-alpha positive breast cancer involves treatment with endocrine therapies, many of which are competitive allosteric regulators that alter transcriptional complex assemblies. These changes in ER-coregulator ensembles recruitment reprogram the transcriptome to elicit anti-cancer phenotypes. While x-ray crystal structures provide snapshots of these allosteric relationships, they limit insights on the protein conformational dynamics that drive therapeutic activities. Understanding how ligands impact ER-alpha LBD structural dynamics will improve our abilities to develop improved therapies and to gain knowledge on how receptor conformational ensembles affect breast cancer phenotypes. To gain these insights, we performed Hydrogen Deuterium Exchange Mass Spectroscopy (HDX-MS) on ER-alpha LBD in complex with structurally distinct therapeutic ligands. These studies show that these different ligands engage unique LBD structural elements beyond what is observed in their x-ray co-crystal structures and are likely to favor the binding of unique coregulator proteins in breast cancer cells.

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Date of Presentation October 17, 2024