Structure and function of Nurr1 identifies a class of ligand-independent nuclear receptors

Nature. 2003 May 29;423(6939):555-60. doi: 10.1038/nature01645.


Members of the nuclear receptor (NR) superfamily of transcription factors modulate gene transcription in response to small lipophilic molecules. Transcriptional activity is regulated by ligands binding to the carboxy-terminal ligand-binding domains (LBDs) of cognate NRs. A subgroup of NRs referred to as 'orphan receptors' lack identified ligands, however, raising issues about the function of their LBDs. Here we report the crystal structure of the LBD of the orphan receptor Nurr1 at 2.2 A resolution. The Nurr1 LBD adopts a canonical protein fold resembling that of agonist-bound, transcriptionally active LBDs in NRs, but the structure has two distinctive features. First, the Nurr1 LBD contains no cavity as a result of the tight packing of side chains from several bulky hydrophobic residues in the region normally occupied by ligands. Second, Nurr1 lacks a 'classical' binding site for coactivators. Despite these differences, the Nurr1 LBD can be regulated in mammalian cells. Notably, transcriptional activity is correlated with the Nurr1 LBD adopting a more stable conformation. Our findings highlight a unique structural class of NRs and define a model for ligand-independent NR function.

Publication types

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

MeSH terms

  • Binding Sites
  • Cell Line
  • Crystallography, X-Ray
  • DNA-Binding Proteins / chemistry*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Regulation
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Ligands
  • Models, Molecular
  • Nuclear Proteins / chemistry*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Nuclear Receptor Subfamily 4, Group A, Member 2
  • Oncogene Proteins / metabolism
  • Organ Specificity
  • Protein Conformation
  • Protein Folding
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-ret
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Signal Transduction
  • Transcription Factors / chemistry*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic*
  • Tumor Cells, Cultured


  • DNA-Binding Proteins
  • Ligands
  • NR4A2 protein, human
  • Nuclear Proteins
  • Nuclear Receptor Subfamily 4, Group A, Member 2
  • Oncogene Proteins
  • Transcription Factors
  • Proto-Oncogene Proteins c-ret
  • RET protein, human
  • Receptor Protein-Tyrosine Kinases

Associated data

  • PDB/1OVL