Crystallographic identification and functional characterization of phospholipids as ligands for the orphan nuclear receptor steroidogenic factor-1.
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.
Li
Yong
Y
Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Avenue, Grand Rapids, MI 49503, USA.
Choi
Mihwa
M
Cavey
Greg
G
Daugherty
Jennifer
J
Suino
Kelly
K
Kovach
Amanda
A
Bingham
Nathan C
NC
Kliewer
Steven A
SA
Xu
H Eric
HE
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D003461:Crystallography; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D051548:Histone Acetyltransferases; D018398:Homeodomain Proteins; D006860:Hydrogen Bonding; D008024:Ligands; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D056920:Nuclear Receptor Coactivator 1; D010743:Phospholipids / Q000378:metabolism*; D011487:Protein Conformation; D018160:Receptors, Cytoplasmic and Nuclear; D017386:Sequence Homology, Amino Acid; D054339:Steroidogenic Factor 1; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D008024:Ligands; D010743:Phospholipids; D018160:Receptors, Cytoplasmic and Nuclear; D054339:Steroidogenic Factor 1; D014157:Transcription Factors; C515058:steroidogenic factor 1, mouse; D051548:Histone Acetyltransferases; C538861:Ncoa1 protein, mouse; D056920:Nuclear Receptor Coactivator 1