Structural analyses reveal phosphatidyl inositols as ligands for the NR5 orphan receptors SF-1 and LRH-1

Cell. 2005 Feb 11;120(3):343-55. doi: 10.1016/j.cell.2005.01.024.


Vertebrate members of the nuclear receptor NR5A subfamily, which includes steroidogenic factor 1 (SF-1) and liver receptor homolog 1 (LRH-1), regulate crucial aspects of development, endocrine homeostasis, and metabolism. Mouse LRH-1 is believed to be a ligand-independent transcription factor with a large and empty hydrophobic pocket. Here we present structural and biochemical data for three other NR5A members-mouse and human SF-1 and human LRH-1-which reveal that these receptors bind phosphatidyl inositol second messengers and that ligand binding is required for maximal activity. Evolutionary analysis of structure-function relationships across the SF-1/LRH-1 subfamily indicates that ligand binding is the ancestral state of NR5A receptors and was uniquely diminished or altered in the rodent LRH-1 lineage. We propose that phospholipids regulate gene expression by directly binding to NR5A nuclear receptors.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Binding Sites / physiology
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • DNA-Binding Proteins / chemistry*
  • DNA-Binding Proteins / metabolism*
  • Evolution, Molecular
  • Homeodomain Proteins
  • Humans
  • Ligands
  • Mice
  • Models, Molecular
  • Phosphatidylinositol Phosphates / chemistry
  • Phosphatidylinositol Phosphates / metabolism
  • Phosphatidylinositols / chemistry
  • Phosphatidylinositols / metabolism*
  • Phylogeny
  • Protein Binding / physiology
  • Protein Structure, Tertiary / physiology
  • Receptors, Cytoplasmic and Nuclear / chemistry*
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Signal Transduction / physiology
  • Steroidogenic Factor 1
  • Transcription Factors / chemistry*
  • Transcription Factors / metabolism*


  • DNA-Binding Proteins
  • Homeodomain Proteins
  • Ligands
  • NR5A1 protein, human
  • NR5A2 protein, human
  • Phosphatidylinositol Phosphates
  • Phosphatidylinositols
  • Receptors, Cytoplasmic and Nuclear
  • Steroidogenic Factor 1
  • Transcription Factors
  • steroidogenic factor 1, mouse

Associated data

  • PDB/1YMT
  • PDB/1YOK
  • PDB/1YOW