Structural overview of the nuclear receptor superfamily: insights into physiology and therapeutics.
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.
Department of Pharmacology, and Center for Molecular Design, University of Virginia Health System, Charlottesville, VA 22908, USA. ph6v@virginia.edu
Pengxiang
P
Huang
Vikas
V
Chandra
Fraydoon
F
Rastinejad
D000595:Amino Acid Sequence; D000818:Animals; D055808:Drug Discovery; D004358:Drug Therapy; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects / Q000502:physiology; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D017433:Protein Structure, Secondary; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000187:drug effects* / Q000502:physiology*; D011960:Receptors, Estrogen / Q000187:drug effects / Q000502:physiology; D011987:Receptors, Steroid / Q000187:drug effects / Q000502:physiology; D011988:Receptors, Thyroid Hormone / Q000187:drug effects / Q000502:physiology
D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone