Estrogen receptor α (ERα) is a ligand-dependent transcription factor that drives most breast cancers. Like other nuclear receptors, ERα is comprised of five modular domains, with the ligand-binding domain (LBD) primarily controlling activation. The LBD is a bundle of 12 α-helices that remodels upon ligand binding to regulate coregulator recruitment. Estrogen binding assembles helices 3, 4, 5, and 12 into a coactivator-binding surface, whereas antagonists reposition helix 12 to block this site and repress transcription. Antagonists include selective estrogen receptor modulators (SERMs), which stabilize ERα and enable tissue-specific agonism, and degraders (SERDs), which promote receptor turnover. LBD crystal structures reveal subtle SERM- vs. SERD-bound differences, but static models miss physiologically relevant dynamics. We hypothesize that ligands across the SERM-to-SERD spectrum remodel ERα dynamics and interdomain signaling via distinct allosteric pathways. ERα’s disordered N-terminal domain complicates purification, and most crystallographic studies of isolated LBD or DBD capture only static snapshots, leaving ligand-specific allosteric changes and interdomain interactions largely unexplored. We combine molecular dynamics with biochemical assays to dissect ligand-specific effects on the ERα LBD dimer for 5 clinically relevant SERMs and SERDs. Simulations map regions of ligand-specific mobility and reveal that SERDs (ICI, RAD1901, and BZA) exhibit greater deviation from the initial crystal structure than SERMs, suggesting distinct conformational landscapes. Residue-level dynamics further highlight pathways of signal propagation across the LBD. Complementary NanoBiT bioluminescence assays detect ligand-specific differences in N- and C-terminal proximities in live cells, and follow-up mutational analyses will validate key residues involved in allosteric signaling. Together, these approaches define how small molecules remodel ERα structure and function, providing mechanistic insights to guide next-generation endocrine therapies.
Fink et al. (Sun,) studied this question.