Agonists and Antagonists of Nuclear Receptors

Nuclear receptors are a family of 48 members present as soluble proteins in the cytosol of cells. They are transcription factors and play an important role in gene regulation. They exist as homo- or heterodimers and are activated by small molecules such as steroid hormones, retinoic acid, fatty acids, triiodothyronine, vitamin D, prostaglandins, bile acids or phospholipids. Structurally, they consist of a ligand-binding and a DNA-binding domain, but additional ligand-independent domains are also involved in the activation of a transcription factor. Their activation is stimulated by agonist binding. They then translocate to the nucleus and recruit coactivators, corepressors and other transcription factors to regulate gene expression. The ligand-binding domains can exhibit impressive selectivity in recognizing their ligands. For example, they detect changes in the substitution patterns of H-bond donor/acceptor functional groups and sense the presence or absence of the 19-methyl group. Binding of agonists and antagonists induces a different orientation of the terminal helix of the ligand binding domain. This helix either opens or closes the entrance to the ligand binding site. Antagonist binding prevents reorientation of this terminal helix across the entrance gate and simultaneously blocks the recognition site for binding of a helical LxxLL motif found on the surface of the coactivator. Agonists and antagonists of steroid receptors are important drugs that interfere with the menstrual cycle as contraceptives, act in anticancer therapy, show anti-inflammatory, immunosuppressive or antiallergic activity at the glucocorticoid receptor, or act as diuretics or hypertensive agents at the mineralocorticoid receptor. The heterodimeric peroxisomal proliferator-activating receptors (PPAR) exist in several subtypes. They recruit the retinoic acid receptor domain to form dimers. Agonists of the PPARγ receptor can induce an increase in glucose metabolism. They are used as insulin sensitizers in the treatment of diabetes. The transcription and expression of cytochrome P450 enzymes involved in the metabolism of xenobiotics can be regulated by the nuclear pregnane X and constitutive androstane receptors (PXR and CAR). These receptors can be activated by a large number of structurally quite different xenobiotics. Their activation leads to increased cytochrome biosynthesis and thus to increased metabolic activity. In contrast to the stereochemically highly specific nuclear steroid receptors, the pregnane X receptor exhibits a pronounced promiscuous binding of structurally highly diverse activators. This property is achieved by an additional highly adaptive structural element present in the PXR receptor. https://sn.pub/l9lvml