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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >The crystal structures of human steroidogenic factor-1 and liver receptor homologue-1
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The crystal structures of human steroidogenic factor-1 and liver receptor homologue-1

机译：人类固醇生成因子1和肝受体同系物1的晶体结构

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摘要

Steroidogenic factor-1 (SF-1) and liver receptor homologue-1 (LRH-1) belong to the fushi tarazu factor 1 subfamily of nuclear receptors. SF-1 is an essential factor for sex determination during development and regulates adrenal and gonadal steroidogenesis in the adult, whereas LRH-1 is a critical factor for development of endodermal tissues and regulates cholesterol and bile acid ho-meostasis. Regulatory ligands are unknown for SF-1 and LRH-1. A reported mouse LRH-1 structure revealed an empty pocket in a region commonly occupied by ligands in the structures of other nuclear receptors, and pocket-filling mutations did not alter the constitutive activity observed. Here we report the crystal structures of the putative ligand-binding domains of human SF-1 at 2.1-A resolution and human LRH-1 at 2.5-A resolution. Both structures bind a coactivator-derived peptide at the canonical activation-function surface, thus adopting the transcriptionally activating conformation. In human LRH-1, coactivator peptide binding also occurs to a second site. We discovered in both structures a phos-pholipid molecule bound in a pocket of the putative ligand-binding domain. MS analysis of the protein samples used for crystallization indicated that the two proteins associate with a range of phos-pholipids. Mutations of the pocket-lining residues reduced the transcriptional activities of SF-1 and LRH-1 in mammalian cell transfection assays without affecting their expression levels. These results suggest that human SF-1 and LRH-1 may be ligand-binding receptors, although it remains to be seen if phospholipids or possibly other molecules regulate SF-1 or LRH-1 under physiological conditions.
机译：类固醇形成因子1（SF-1）和肝受体同源物1（LRH-1）属于核受体的fushi tarazu因子1亚家族。 SF-1是发育过程中决定性别的重要因素，并调节成年人的肾上腺和性腺类固醇生成，而LRH-1是发育内胚层组织的关键因素，并调节胆固醇和胆汁酸的稳态。 SF-1和LRH-1的调节配体未知。报道的小鼠LRH-1结构揭示了在其他核受体结构中通常被配体占据的区域中有一个空袋，并且袋填充突变并未改变所观察到的组成活性。在这里我们报告人类SF-1在2.1-A分辨率和人类LRH-1在2.5-A分辨率的推定配体结合域的晶体结构。两种结构都在规范的激活功能表面结合了共激活因子衍生的肽，因此采用了转录激活构象。在人类LRH-1中，辅助激活肽的结合也发生在第二个位点。我们在这两个结构中发现了一个磷脂分子，该分子结合在推定的配体结合域的口袋中。对用于结晶的蛋白质样品的MS分析表明，这两种蛋白质与一定范围的磷脂缔合。口袋衬里残基的突变降低了哺乳动物细胞转染试验中SF-1和LRH-1的转录活性，而不会影响它们的表达水平。这些结果表明人SF-1和LRH-1可能是配体结合受体，尽管在生理条件下磷脂或可能的其他分子是否调节SF-1或LRH-1仍有待观察。

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