Modulation of human nuclear receptor LRH-1 activity by phospholipids and SHP

Nat Struct Mol Biol. 2005 Apr;12(4):357-63. doi: 10.1038/nsmb910. Epub 2005 Feb 22.


The human nuclear receptor liver receptor homolog 1 (hLRH-1) plays an important role in the development of breast carcinomas. This orphan receptor is efficiently downregulated by the unusual co-repressor SHP and has been thought to be ligand-independent. We present the crystal structure at a resolution of 1.9 A of the ligand-binding domain of hLRH-1 in complex with the NR box 1 motif of human SHP, which we find contacts the AF-2 region of hLRH-1 using selective structural motifs. Electron density indicates phospholipid bound within the ligand-binding pocket, which we confirm using mass spectrometry of solvent-extracted samples. We further show that pocket mutations reduce phospholipid binding and receptor activity in vivo. Our results indicate that hLRH-1's control of gene expression is mediated by phospholipid binding, and establish hLRH-1 as a novel target for compounds designed to slow breast cancer development.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Crystallography, X-Ray
  • DNA-Binding Proteins / chemistry*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Regulation
  • HeLa Cells
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Phospholipids / chemistry
  • Phospholipids / metabolism
  • Phospholipids / pharmacology*
  • Protein Binding
  • Protein Structure, Tertiary
  • Receptors, Cytoplasmic and Nuclear / chemistry*
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Sequence Alignment
  • Spectrometry, Mass, Electrospray Ionization
  • Transcription Factors


  • DNA-Binding Proteins
  • NR5A2 protein, human
  • Phospholipids
  • Receptors, Cytoplasmic and Nuclear
  • Transcription Factors
  • nuclear receptor subfamily 0, group B, member 2

Associated data

  • PDB/1YUC