Orphan nuclear receptors adopted by crystallography

Curr Opin Struct Biol. 2005 Dec;15(6):708-15. doi: 10.1016/j.sbi.2005.10.009. Epub 2005 Nov 2.


Of the large nuclear hormone receptor superfamily of proteins, orphan nuclear receptors have remained a mystery owing to their lack of identified ligands and their constitutive nature. Now, structures of several ligand-binding domains of orphan receptors have provided some surprising insights that were not anticipated from molecular studies. Therefore, most orphan nuclear receptors have now been 'adopted' and their regulation has been shown to range from true ligand-independence to highly promiscuous ligand-dependence. Former orphan receptors have been found to contain ligand-binding pockets that range in volume from vast (>1600A3) to non-existent and have been shown to generate surface AF2 motifs that range from being multifunctionally active to distinctly inactive. Insights from these new structures illustrate how powerful a structural biology approach can be when integrated with molecular and cellular physiology.

Publication types

  • Review

MeSH terms

  • Animals
  • Binding Sites
  • Crystallography, X-Ray
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / metabolism*
  • Homeodomain Proteins / chemistry
  • Homeodomain Proteins / metabolism*
  • Humans
  • Ligands
  • Models, Molecular*
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Pregnane X Receptor
  • Protein Conformation
  • Receptors, Cytoplasmic and Nuclear / chemistry
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Receptors, Steroid / chemistry
  • Receptors, Steroid / metabolism*
  • Species Specificity
  • Steroidogenic Factor 1
  • Transcription Factors / chemistry
  • Transcription Factors / metabolism*


  • DNA-Binding Proteins
  • Homeodomain Proteins
  • Ligands
  • NR4A1 protein, human
  • NR5A2 protein, human
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Pregnane X Receptor
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Steroid
  • Steroidogenic Factor 1
  • Transcription Factors