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.

雌激素相关受体β（ERRβ）是许多生物过程中至关重要的核受体。尽管ERRβ具有重要的生物学和药学意义，但由于难以获得用于结构研究的纯净稳定的蛋白质，因此难以理解ERRβ的结构。实际上，ERRβ配体结合域仍然是最后一个未解决的ERR结构，也是少数几个未知的核受体结构之一。在这里，我们报告了一个关键的单残基突变的鉴定，该突变导致了有效的ERRβ配体结合域的稳固溶解性和稳定性，从而提供了一种蛋白质工具，使该探针能够首次对该重要受体的生化和结构研究进行探索。