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

Yong Li, Mihwa Choi, Greg Cavey, Jennifer Daugherty, Kelly Suino, Amanda Kovach, Nathan C. Bingham, Steven A. Kliewer, H. Eric Xu

Research output: Contribution to journalArticle

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Abstract

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 Å 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 (∼1600 Å3), 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.

Original languageEnglish (US)
Pages (from-to)491-502
Number of pages12
JournalMolecular Cell
Volume17
Issue number4
DOIs
StatePublished - Feb 18 2005

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Steroidogenic Factor 1
Orphan Nuclear Receptors
Phospholipids
Ligands
Endocrine Glands
Hydrogen
Mutation

ASJC Scopus subject areas

  • Molecular Biology

Cite this

Crystallographic identification and functional characterization of phospholipids as ligands for the orphan nuclear receptor steroidogenic factor-1. / Li, Yong; Choi, Mihwa; Cavey, Greg; Daugherty, Jennifer; Suino, Kelly; Kovach, Amanda; Bingham, Nathan C.; Kliewer, Steven A.; Xu, H. Eric.

In: Molecular Cell, Vol. 17, No. 4, 18.02.2005, p. 491-502.

Research output: Contribution to journalArticle

Li, Yong ; Choi, Mihwa ; Cavey, Greg ; Daugherty, Jennifer ; Suino, Kelly ; Kovach, Amanda ; Bingham, Nathan C. ; Kliewer, Steven A. ; Xu, H. Eric. / Crystallographic identification and functional characterization of phospholipids as ligands for the orphan nuclear receptor steroidogenic factor-1. In: Molecular Cell. 2005 ; Vol. 17, No. 4. pp. 491-502.
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