X-ray structure of the hRORα LBD at 1.63 Å:: Structural and functional data that cholesterol or a cholesterol derivative is the natural ligand of RORα
X-ray structure of the hRORα LBD at 1.63 Å:: Structural and functional data that cholesterol or a cholesterol derivative is the natural ligand of RORα
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DOI：
10.1016/s0969-2126(02)00912-7
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发表时间：
2002-12-01
期刊：
影响因子：
5.7
通讯作者：
Fournier, B
中科院分区：
文献类型：
--
作者：
Kallen, JA;Schlaeppi, JM;Fournier, B
视黄酸相关孤儿受体α（ROR α）是核激素受体亚家族1的孤儿成员。到目前为止，还没有ROR α的X射线结构被描述，也没有配体被鉴定。我们描述了ROR α的配体结合结构域（LBD）的第一个晶体结构，分辨率为1.63埃。该结构揭示了存在于配体结合口袋（LBP）中的配体，其通过X射线晶体学鉴定为胆甾-5-烯-3 β-of（胆固醇）。此外，ROR α转录活性可以通过细胞内胆固醇水平的变化或参与胆固醇结合的残基的突变来调节。这些发现表明，ROR α可以在胆固醇稳态的调节中发挥关键作用，因此代表了胆固醇相关疾病的重要药物靶点。
The retinoic acid-related orphan receptor alpha (RORalpha) is an orphan member of the subfamily 1 of nuclear hormone receptors. No X-ray structure of RORalpha has been described so far, and no ligand has been identified-We describe the first crystal structure of the ligand binding domain (LBD) of RORalpha, at 1.63 Angstrom resolution. This structure revealed a ligand present in the ligand binding pocket (LBP), which was identified by X-ray crystallography as cholest-5-en-3beta-of (cholesterol). Moreover, RORalpha transcriptional activity could be modulated by changes in intracellular cholesterol level or mutation of residues involved in cholesterol binding. These findings suggest that RORalpha could play a key role in the regulation of cholesterol homeostasis and thus represents an important drug target in cholesterol-related diseases.