Crystallographic Identification and Functional Characterization of Phospholipids as Ligands for the Orphan Nuclear Receptor Steroidogenic Factor-1
- Van Andel
The orphan nuclear receptor steroidogenic factor 1 (SF-1) regulates the differentiation and function of endocrine glands. Although SF-1 is constitutively active in cell-based assays, it is not known whether this transcriptional activity is modulated by ligands. Here, we describe the 1.5 {angstrom} crystal structure of the SF-1 ligand binding domain in complex with an LXXLL motif from a coregulator protein. The structure reveals the presence of a phospholipid ligand in a surprisingly large pocket ({approx}1600 {angstrom}{sup 3}), with the receptor adopting the canonical active conformation. The bound phospholipid is readily exchanged and modulates SF-1 interactions with coactivators. Mutations designed to reduce the size of the SF-1 pocket or to disrupt hydrogen bonds with the phospholipid abolish SF-1/coactivator interactions and significantly reduce SF-1 transcriptional activity. These findings provide evidence that SF-1 is regulated by endogenous ligands and suggest an unexpected relationship between phospholipids and endocrine development and function.
- Research Organization:
- Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Organization:
- USDOE
- OSTI ID:
- 1008496
- Journal Information:
- Mol. Cell, Vol. 17, Issue 02, 2005; ISSN 1097-2765
- Country of Publication:
- United States
- Language:
- ENGLISH
Similar Records
The Orphan Nuclear Receptor TR4 Is a Vitamin A-activated Nuclear Receptor
Structure and Dynamics of the Liver Receptor Homolog 1–PGC1 α Complex