The nuclear receptor superfamily: A structural perspective

• Published in: Protein science Vol. 27; no. 11; pp. 1876 - 1892
• Main Authors: Weikum, Emily R., Liu, Xu, Ortlund, Eric A.
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.11.2018; Wiley Subscription Services, Inc
• Subjects: Allosteric properties; Amino Acids - chemistry; Base Sequence; Chromatin; Chromatin - metabolism; Circadian rhythms; co‐regulator; Deoxyribonucleic acid; DNA; DNA - metabolism; DNA binding domain; Drug development; Gene expression; Gene Expression Regulation - drug effects; Gene sequencing; Humans; Inflammatory diseases; ligand binding domain; Ligands; Lipid metabolism; Lipid Metabolism - drug effects; Lipids; Lipids - genetics; Lipophilic; Metabolic disorders; Metabolism; nuclear receptor; Nuclear receptors; Nucleotide sequence; Physiological effects; Protein Binding; Protein Conformation; Receptors; Receptors, Cytoplasmic and Nuclear - metabolism; Regulators; Review; Reviews; Signal Transduction; Signaling; Therapeutic applications; transactivation; Transcription factors; transrepression; transrepression; nuclear receptor; DNA binding domain; co-regulator; ligand binding domain; transactivation
• ISSN: 0961-8368; 1469-896X
• DOI: 10.1002/pro.3496

Nuclear receptors (NRs) are a family of transcription factors that regulate numerous physiological processes such as metabolism, reproduction, inflammation, as well as the circadian rhythm. NRs sense changes in lipid metabolite levels to drive differential gene expression, producing distinct physiologic effects. This is an allosteric process whereby binding a cognate ligand and specific DNA sequences drives the recruitment of diverse transcriptional co‐regulators at chromatin and ultimately transactivation or transrepression of target genes. Dysregulation of NR signaling leads to various malignances, metabolic disorders, and inflammatory disease. Given their important role in physiology and ability to respond to small lipophilic ligands, NRs have emerged as valuable therapeutic targets. Here, we summarize and discuss the recent progress on understanding the complex mechanism of action of NRs, primarily from a structural perspective. Finally, we suggest future studies to improve our understanding of NR signaling and better design drugs by integrating multiple structural and biophysical approaches.