Structural determinants of pure antiestrogenicity
bioRxiv (Cold Spring Harbor Laboratory)(2023)
Abstract
Inhibitory activities of antiestrogens on estrogen receptor alpha (ERα) range from mixed antagonism/agonism (selective ER modulators; SERMs) to complete antiestrogenicity associated with accelerated ERα turnover (selective ER degraders; SERDs). Here, we show using a panel of SERMs, SERDs and a PROTAC that efficient induction of ERα SUMOylation better accounts for complete transcriptional repression than increased suppression of coactivator recruitment or accelerated ERα degradation. Antiestrogen-induced ERα 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 ERα LBD bound to fulvestrant analogs and molecular dynamics simulations predict dynamic side chain interactions with wild-type ERα 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 ERα activity and provide insights into its structural determinants.
### Competing Interest Statement
The authors have declared no competing interest.
MoreTranslated text
Key words
pure antiestrogenicity,structural determinants
AI Read Science
Must-Reading Tree
Example
![](https://originalfileserver.aminer.cn/sys/aminer/pubs/mrt_preview.jpeg)
Generate MRT to find the research sequence of this paper
Chat Paper
Summary is being generated by the instructions you defined