Structural determinants of pure antiestrogenicity

Abstract

Inhibitory activities of antiestrogens on estrogen receptor alpha (ER) range from mixed antagonism/agonism (selective ER modulators; SERMs) to complete antiestrogenicity associated with accelerated ER turnover (selective ER degraders; SERDs). Here, we show using a panel of SERMs, SERDs and a PROTAC that efficient induction of ER SUMOylation better accounts for complete transcriptional repression than increased suppression of coactivator recruitment or accelerated ER degradation. Antiestrogen-induced ER SUMOylation depends on the hydrophobicity of N-terminal residues of ligand binding domain (LBD) helix 12 (H12). L536 mutations, including those occurring in endocrine therapy-resistant breast cancer, abolished SUMOylation with all antiestrogens. Structures of the L536S human ER LBD bound to fulvestrant analogs and molecular dynamics simulations predict dynamic side chain interactions with wild-type ER H12 in the coactivator-binding groove and model the impact of L536 mutations. Together, our results show that induced SUMOylation contributes to the complete suppression of ER activity and provide insights into its structural determinants.