1ZDU

The Crystal Structure of Human Liver Receptor Homologue-1

Summary for 1ZDU

• Entry DOI: 10.2210/pdb1zdu/pdb
• Related: 1ZDT
• Descriptor: Orphan nuclear receptor NR5A2, Nuclear receptor coactivator 2, PHOSPHATIDYLGLYCEROL-PHOSPHOGLYCEROL, ... (5 entities in total)
• Functional Keywords: liver receptor homologue-1, lrh-1, nuclear receptor, phospholipid, phosphatidylethanolamine, transcription
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus (Probable): O00482; Nucleus: Q15596
• Total number of polymer chains: 3
• Total formula weight: 32008.00

Authors

Wang, W.,Zhang, C.,Marimuthu, A.,Krupka, H.I.,Tabrizizad, M.,Shelloe, R.,Mehra, U.,Eng, K.,Nguyen, H.,Settachatgul, C.,Powell, B.,Milburn, M.V.,West, B.L. (deposition date: 2005-04-14, release date: 2005-05-24, Last modification date: 2024-02-14)

Primary citation

Wang, W.,Zhang, C.,Marimuthu, A.,Krupka, H.I.,Tabrizizad, M.,Shelloe, R.,Mehra, U.,Eng, K.,Nguyen, H.,Settachatgul, C.,Powell, B.,Milburn, M.V.,West, B.L.
The crystal structures of human steroidogenic factor-1 and liver receptor homologue-1
Proc.Natl.Acad.Sci.USA, 102:7505-7510, 2005

PubMed Abstract: 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 homeostasis. 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 phospholipid 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 phospholipids. 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.

PubMed: 15897460
DOI: 10.1073/pnas.0409482102

Experimental method

X-RAY DIFFRACTION (2.5 Å)