Abstract
Nuclear receptors (NRs) are ligand-activated transcription factors that regulate the expression of their target genes. NRs play important roles in many human diseases, including metabolic diseases and cancer, and are therefore a key class of therapeutic targets. Steroids play important roles in regulating nuclear receptors; in addition to being ligands of steroid receptors, steroids (and their metabolites) also regulate other NRs, such as the pregnane X receptor and constitutive androstane receptor (termed xenobiotic receptors), which participate in steroid metabolism. Xenobiotic receptors have promiscuous ligand-binding properties, and their structurally diverse ligands include steroids and their metabolites. Therefore, steroids, their metabolism and metabolites, xenobiotic receptors, steroid receptors, and the respective signaling pathways they regulate have functional interactions. This review discusses these functional interactions and their implications for activities mediated by steroid receptors and xenobiotic receptors, focusing on steroids that modulate pathways involving the pregnane X receptor and constitutive androstane receptor. The emphasis of the review is on structure-function studies of xenobiotic receptors bound to steroid ligands.
Highlights
Nuclear receptors (NRs) are ligand-activated transcription factors that regulate the expression of their target genes
NRs is the DNA-binding domain (DBD), which consists of 70 amino acid residues and zinc-finger motifs that are crucial for DNA recognition and transcription [5]
This review focuses on the xenobiotic nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR), summarizing advances in the discovery of steroid ligands that modulate their activity and structure-function studies of these receptors bound to steroids
Summary
Nuclear receptors (NRs) function as transcription factors. When activated by binding to their ligands, NRs bind to DNA promoter regions to activate the expression of target genes [1]. Among the different structural elements of NRs, the C-terminal ligand-binding domain (LBD), which is important for the binding of small molecules such as steroids, is the region of interest for small molecule–based drug discovery. NRs bind to diverse ligands, including steroids Small lipophilic molecules, such as steroids and thyroid hormones, are significant in the growth, differentiation, metabolism, reproduction, and morphogenesis of higher organisms and humans. The activity of NRs can be modulated by small molecules, and NRs can be used successfully as drug targets [2,6,7] Small molecules such as steroid ligands play an important role in modulating NR signaling pathways; further investigation of steroid ligands and their interaction with specific NRs will have pharmacological and therapeutic relevance. This review focuses on the xenobiotic nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR), summarizing advances in the discovery of steroid ligands that modulate their activity and structure-function studies of these receptors bound to steroids
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