Structural Insights into the Specificity of Ligand Binding and Coactivator Assembly by Estrogen-Related Receptor β. Issue 19 (4th September 2020)

• Record Type: Journal Article
• Authors: Yao, Benqiang; Zhang, Shuchi; Wei, Yijuan; Tian, Siyu; Lu, Zhou; Jin, Lihua; He, Ying; Xie, Wen; Li, Yong
• Is Part Of: Journal of molecular biology. Volume 432:Issue 19(2020)
• Page Start: 5460
• Page End: 5472
• Publication Date: 2020-09-04
• Subjects: ERR estrogen-related receptor -- RORγ retinoic-acid-receptor-related orphan nuclear receptor gamma -- LRH-1 liver receptor homolog-1 -- SF-1 steroidogenic factor 1 -- LBD ligand-binding domain -- SRC steroid receptor coactivator -- PGC-1α peroxisome proliferator-activated receptor gamma coactivator 1α -- DES diethylstilbestrol -- 4-OHT 4-hydroxytamoxifen -- BPA bisphenol A -- WT wild-type -- LBP ligand binding pocket; nuclear receptor ERRβ -- crystal structures -- ligand recognition -- coactivator binding -- transcriptional regulation; Molecular biology -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Bacteriology -- Periodicals; Molecular Biology -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biologie -- Périodiques; Biochimie -- Périodiques; Moleculaire biologie; Biochemistry; Biology; Molecular biology; Periodicals; 572.805
• DOI: 10.1016/j.jmb.2020.08.007
• Languages: English
• ISSNs: 0022-2836

Abstract

Abstract: Estrogen-related receptor β (ERRβ) is a nuclear receptor critical for many biological processes. Despite the biological and pharmaceutical importance of ERRβ, deciphering the structure of ERRβ has been hampered by the difficulties in obtaining a pure and stable protein for structural studies. In fact, the ERRβ ligand-binding domain remains the last unsolved ERR structure and also one of only a few unknown nuclear receptor structures. Here, we report the identification of a critical single-residue mutation resulted in robust solubility and stability of an active ERRβ ligand-binding domain, thereby providing a protein tool enabling the first probe into the biochemical and structural studies of this important receptor. The crystal structure reveals key structural features that have enabled the integration of the molecular determinants of signals transduced across the ligand binding and coregulator recruitment by all three ERR subtypes, which also provides a framework for the rational design of selective and potent ligands for the treatment of various ERR-mediated diseases. Graphical Abstract: Unlabelled Image Highlights: We report the first crystal structure of the estrogen-related receptor β (ERRβ) ligand-binding domain. We reveal a critical single-residue mutation on the ERRβ resulted in robust solubility of an active protein for biochemical and structural studies. We reveal two endocrine-disrupting chemicals, BPA and 4-OHT, as ERRβ ligands, providing a mechanistic understanding for environmental risk assessments. The mechanisms of hormone recognition and coactivator assembly may lead to a structural template for designing novel compounds selectively targeting individual ERR subtype in treating ERR-mediated diseases.