Crystallographic identification and functional characterization of phospholipids as ligands for the orphan nuclear receptor steroidogenic factor-1.

Li Y, Choi M, Cavey G, Daugherty J, Suino K, Kovach A, Bingham NC, Kliewer SA, Xu HE
Mol Cell. 2005 17 (4): 491-502

PMID: 15721253 · DOI:10.1016/j.molcel.2005.02.002

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 angstroms 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 (approximately 1600 angstroms3), 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.

MeSH Terms (20)

Amino Acid Sequence Animals Binding Sites Crystallography DNA-Binding Proteins Histone Acetyltransferases Homeodomain Proteins Hydrogen Bonding Ligands Mice Molecular Sequence Data Mutation Nuclear Receptor Coactivator 1 Phospholipids Protein Conformation Receptors, Cytoplasmic and Nuclear Sequence Homology, Amino Acid Steroidogenic Factor 1 Transcription, Genetic Transcription Factors

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