Structural overview of the nuclear receptor superfamily: insights into physiology and therapeutics

Annu Rev Physiol. 2010;72:247-72. doi: 10.1146/annurev-physiol-021909-135917.


As ligand-regulated transcription factors, the nuclear hormone receptors are nearly ideal drug targets, with internal pockets that bind to hydrophobic, drug-like molecules and well-characterized ligand-induced conformational changes that recruit transcriptional coregulators to promoter elements. Yet, due to the multitude of genes under the control of a single receptor, the major challenge has been the identification of ligands with gene-selective actions, impacting disease outcomes through a narrow subset of target genes and not across their entire gene-regulatory repertoire. Here, we summarize the concepts and work to date underlying the development of steroidal and nonsteroidal receptor ligands, including the use of crystal structures, high-throughput screens, and rational design approaches for finding useful therapeutic molecules. Difficulties in finding selective receptor modulators require a more complete understanding of receptor interdomain communications, posttranslational modifications, and receptor-protein interactions that could be exploited for target gene selectivity.

Publication types

  • Review

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Drug Discovery*
  • Drug Therapy*
  • Humans
  • Lipid Metabolism / drug effects
  • Lipid Metabolism / physiology
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / metabolism
  • Nuclear Proteins / physiology*
  • Protein Structure, Secondary
  • Receptors, Cytoplasmic and Nuclear / chemistry
  • Receptors, Cytoplasmic and Nuclear / drug effects*
  • Receptors, Cytoplasmic and Nuclear / physiology*
  • Receptors, Estrogen / drug effects
  • Receptors, Estrogen / physiology
  • Receptors, Steroid / drug effects
  • Receptors, Steroid / physiology
  • Receptors, Thyroid Hormone / drug effects
  • Receptors, Thyroid Hormone / physiology


  • Nuclear Proteins
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Estrogen
  • Receptors, Steroid
  • Receptors, Thyroid Hormone