Structural insights into gene repression by the orphan nuclear receptor SHP

Proc Natl Acad Sci U S A. 2014 Jan 14;111(2):839-44. doi: 10.1073/pnas.1322827111. Epub 2013 Dec 30.


Small heterodimer partner (SHP) is an orphan nuclear receptor that functions as a transcriptional repressor to regulate bile acid and cholesterol homeostasis. Although the precise mechanism whereby SHP represses transcription is not known, E1A-like inhibitor of differentiation (EID1) was isolated as a SHP-interacting protein and implicated in SHP repression. Here we present the crystal structure of SHP in complex with EID1, which reveals an unexpected EID1-binding site on SHP. Unlike the classical cofactor-binding site near the C-terminal helix H12, the EID1-binding site is located at the N terminus of the receptor, where EID1 mimics helix H1 of the nuclear receptor ligand-binding domain. The residues composing the SHP-EID1 interface are highly conserved. Their mutation diminishes SHP-EID1 interactions and affects SHP repressor activity. Together, these results provide important structural insights into SHP cofactor recruitment and repressor function and reveal a conserved protein interface that is likely to have broad implications for transcriptional repression by orphan nuclear receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bile Acids and Salts / metabolism
  • Binding Sites / genetics
  • Cell Cycle Proteins
  • Cell Line
  • Cholesterol / metabolism
  • Crystallization
  • Drug Design
  • Homeostasis / genetics
  • Homeostasis / physiology
  • Humans
  • Models, Molecular*
  • Nuclear Proteins / chemistry*
  • Protein Conformation*
  • Receptors, Cytoplasmic and Nuclear / chemistry*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Repressor Proteins / chemistry*


  • Bile Acids and Salts
  • Cell Cycle Proteins
  • EID1 protein, human
  • Nuclear Proteins
  • Receptors, Cytoplasmic and Nuclear
  • Repressor Proteins
  • nuclear receptor subfamily 0, group B, member 2
  • Cholesterol

Associated data

  • PDB/4NUF