Structural basis for ligand-independent activation of the orphan nuclear receptor LRH-1
Structural basis for ligand-independent activation of the orphan nuclear receptor LRH-1
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DOI：
10.1016/s1097-2765(03)00236-3
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发表时间：
2003-06-01
期刊：
影响因子：
16
通讯作者：
Ingraham, HA
中科院分区：
文献类型：
--
作者：
Sablin, EP;Krylova, IN;Ingraham, HA
孤儿核受体 SF-1 和 LRH-1 具有组成型活性，但仍不确定它们的激活是否具有激素依赖性。我们报告了 LRH-1 配体结合结构域的晶体结构，分辨率为 2.4 埃，并发现该受体是一种单体，采用具有大但空的疏水袋的活性构象。在这个口袋中添加庞大的侧链会导致完全或更大的活性，这表明虽然 LRH-1 可以容纳潜在的配体，但这些对于基础活性来说是可有可无的。 LRH-1 的组成活性似乎是由一个独特的结构元件赋予的，该结构元件由延伸的螺旋 2 组成，为典型的 LBD 折叠提供了一个附加层。突变螺旋 2 中的保守精氨酸会降低 LRH-1 受体活性和辅助调节因子的招募，这与类似的 SF-1 人类突变体所表现出的部分功能丧失表型一致。这些发现说明了在没有配体结合的情况下核受体稳定的替代结构策略。
The orphan nuclear receptors SF-1 and LRH-1 are constitutively active, but it remains uncertain whether their activation is hormone dependent. We report the crystal structure of the LRH-1 ligand binding domain to 2.4 Angstrom resolution and find the receptor to be a monomer that adopts an active conformation with a large but empty hydrophobic pocket. Adding bulky side chains into this pocket resulted in full or greater activity suggesting that, while LRH-1 could accommodate potential ligands, these are dispensable for basal activity. Constitutive LRH-1 activity appears to be conferred by a distinct structural element consisting of an extended helix 2 that provides an additional layer to the canonical LBD fold. Mutating the conserved arginine in helix 2 reduced LRH-1 receptor activity and coregulator recruitment, consistent with the partial loss-of-function phenotype exhibited by an analogous SF-1 human mutant. These findings illustrate an alternative structural strategy for nuclear receptor stabilization in the absence of ligand binding.