General molecular biology and architecture of nuclear receptors

Abstract

Nuclear receptors (NRs) regulate and coordinate multiple processes by integrating internal and external signals, thereby maintaining homeostasis in front of nutritional, behavioral and environmental challenges. NRs exhibit strong similarities in their structure and mode of action: by selective transcriptional activation or repression of cognate target genes, which can either be controlled through a direct, DNA binding-dependent mechanism or through crosstalk with other transcriptional regulators, NRs modulate the expression of gene clusters thus achieving coordinated tissue responses. Additionally, non genomic effects of NR ligands appear mediated by ill-defined mechanisms at the plasma membrane. These effects mediate potential therapeutic effects as small lipophilic molecule targets, and many efforts have been put in elucidating their precise mechanism of action and pathophysiological roles. Currently, numerous nuclear receptor ligand analogs are used in therapy or are tested in clinical trials against various diseases such as hypertriglyceridemia, atherosclerosis, diabetes, allergies and cancer and others.

Figure 1. General structural organization of nuclear receptors

Letters from A to F represent nuclear receptor domains from N-terminus to C-terminus of the nuclear receptor respectively. The structure and functions of each domain is detailed in the text.

Figure 2. Crystal structure of PPARγ-RXRα complex bound to a DR-1 response element

Crystallographic coordinates were obtained from the RCSB protein databank (PDB 3E00) and visualized using the Jmol software. PPARγ is purple and RXRα is blue.

Figure 3. Different architecture of selected response elements of nuclear receptors

IR -inverted repeat, ER - everted repeat, DR - direct repeat, ‘N’ indicates any nucleotide, “n” indicates negative response elements.

Figure 4. General mechanism of NR action

Nuclear receptors may act in two different ways. Upon ligand binding nuclear receptors forming heterodimers with RXR interact with a specific positive gene response element (pRE) and activate mRNA transcription of target genes. Alternatively, they may interact directly with repressive, negative response elements (nRE). The major suppressive effect of nuclear receptors is however thought to be mediated by monomers interaction with subunits of AP-1 and NF-kB transcription factors, and hamper the expression of inflammatory-related genes (see text for details).