Bisphenol a derivatives act as novel coactivator-binding inhibitors for estrogen receptor β

Masaki Iwamoto, Takahiro Masuya, Mari Hosose, Koki Tagawa, Tomoka Ishibashi, Keitaro Suyama, Takeru Nose, Eiji Yoshihara, Michael Downes, Ronald M. Evans, Ayami Matsushima

研究成果: Contribution to journalArticle査読

抄録

Bisphenol A and its derivatives are recognized as endocrine disruptors based on their complex effects on estrogen receptor (ER) signaling. While the effects of bisphenol derivatives on ERα have been thoroughly evaluated, how these chemicals affect ERβ signaling is less well understood. Herein, we sought to identify novel ERβ ligands using a radioligand competitive binding assay to screen a chemical library of bisphenol derivatives. Many of the compounds identified showed intriguing dual activities as both ERα agonists and ERβ antagonists. Docking simulations of these compounds and ERβ suggested that they bound not only to the canonical binding site of ERβ but also to the coactivator binding site located on the surface of the receptor, suggesting that they act as coactivator-binding inhibitors (CBIs). Receptor–ligand binding experiments using WT and mutated ERβ support the presence of a second ligand-interaction position at the coactivator-binding site in ERβ, and direct binding experiments of ERβ and a coactivator peptide confirmed that these compounds act as CBIs. Our study is the first to propose that bisphenol derivatives act as CBIs, presenting critical insight for the future development of ER signaling–based drugs and their potential to function as endocrine disruptors.

本文言語英語
論文番号101173
ジャーナルJournal of Biological Chemistry
297
5
DOI
出版ステータス出版済み - 11 1 2021

All Science Journal Classification (ASJC) codes

  • 生化学
  • 分子生物学
  • 細胞生物学

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