Structural Basis for Hydroxycholesterols as Natural Ligands of Orphan Nuclear Receptor RORγ
Structural Basis for Hydroxycholesterols as Natural Ligands of Orphan Nuclear Receptor RORγ
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DOI：
10.1210/me.2009-0507
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发表时间：
2010-05-01
影响因子：
--
通讯作者：
Li, Yong
中科院分区：
文献类型：
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作者：
Jin, Lihua;Martynowski, Dariusz;Li, Yong
维甲酸相关孤儿受体γ（ROR γ）在发育和代谢稳态中具有重要作用。虽然ROR γ的生物学功能已被广泛研究，但尚未鉴定出ROR γ的配体，也未报道ROR γ的结构。在这项研究中，我们表明，羟基胆固醇促进招聘的辅激活ROR γ使用生化测定。我们还报告了与羟基胆固醇结合的ROR γ配体结合结构域的晶体结构。这些结构揭示了ROR γ口袋中各种羟基胆固醇的结合模式，受体均采用典型的活性构象。破坏羟基胆固醇结合的突变消除了ROR γ的组成性活性。我们的观察表明内源性羟基胆固醇在调节ROR γ 6依赖性生物过程中起重要作用。（分子内分泌学24：923-929，2010）
The retinoic acid-related orphan receptor gamma (ROR gamma) has important roles in development and metabolic homeostasis. Although the biological functions of ROR gamma have been studied extensively, no ligands for ROR gamma have been identified, and no structure of ROR gamma has been reported. In this study, we showed that hydroxycholesterols promote the recruitment of coactivators by ROR gamma using biochemical assays. We also report the crystal structures of the ROR gamma ligand-binding domain bound with hydroxycholesterols. The structures reveal the binding modes of various hydroxycholesterols in the ROR gamma pocket, with the receptors all adopting the canonical active conformation. Mutations that disrupt the binding of hydroxycholesterols abolish the constitutive activity of ROR gamma. Our observations suggest an important role for the endogenous hydroxycholesterols in modulating ROR gamma 6-dependent biological processes. (Molecular Endocrinology 24: 923-929, 2010)