2.25 – Nuclear Hormone Receptors

The human nuclear receptor (NR) superfamily consists of 49 documented proteins that regulate many aspects of development, metabolism, and inflammation. These receptors share a remarkably similar protein structure, especially within their DNA-binding domains (DBDs) and the ligand-binding domains (LBDs). Given their protein structure similarities and the nature of their overlapping functions it has been speculated that the family evolved as a means to promote survival of the organism: acquiring or managing energy stores, metabolic rates, salt homeostasis, responding to environmental toxins and inflammation, and regulating reproduction and development. NRs function, in part, through ligand binding and subsequent activation of their transcriptional activity (ability to regulate expression of target genes). Lipophilic, extracellular ligands include some well-known hormonal molecules such as steroids, retinoids, thyroid hormone, and vitamin D3. The family is loosely grouped into three classes based on ligand and DNA binding, and on the nature of the unliganded protein. Class I NRs are the classic steroid hormone receptors that include the estrogen receptor (ER), androgen receptor (AR), progesterone receptor (PR), glucocorticoid receptor (GR), and the mineralocorticoid receptor (MR). In the absence of ligand, these NRs are sequestered in nonfunctional complexes with heat-shock proteins and are transcriptionally inactive. Upon ligand activation, Class I nuclear receptors bind DNA as homodimers. Class II receptors include thyroid hormone receptor (TR), vitamin D receptor (VDR), retinoid A receptor (RAR), peroxisome proliferator-activated receptor (PPAR), farnesoid X receptor (FXR), constitutive androstane receptor (CAR), and pregnane X receptor (PXR). These receptors form heterodimers with the retinoid X receptor (RXR), even in absence of ligand, and exert a repressive silencing effect on basal promoter activity that is reversed upon ligand binding. Importantly, these proteins possess ligand-binding pockets (LBP) within the LBD that are relatively large, compared with the steroid receptors, suggesting different modes of cellular function via low affinity and structurally diverse ligands. Class III receptors comprise the ‘orphan nuclear receptors’ (oNRs) because they lack known physiological ligands. The functional activity of an NR is not only regulated by steroid hormones or other endogenous lipophilic ligands, but also by a complex array of regulatory proteins, including corepressors, coactivators, and chromatin modifiers. The transcription and subsequent expression of NR-dependent genes is a dynamic process with continual exchange and turnover of NRs, coregulators, and other components of the transcriptional machinery. Once recruited, coregulators and NRs cycle on and off the target promoter many times, interacting only briefly with the regulatory elements. The NRs and their coregulators are also subjected to rapid modifications, including ubiquitination, phosphorylation, acetylation, and methylation. Not surprisingly, these NRs offer an ever-expanding range of targets for pharmacological intervention and development of therapeutics. Two of the most prominent drug classes, the hypolipidemic fibrate class of drugs and the insulin-sensitizing type 2 diabetes drugs, the glitazones, target PPAR nuclear receptors. The identification of natural/endogenous ligands for what once were orphan NRs, and development of synthetic agonists and antagonists, has also enabled significant advances in our understanding of the roles of the NR superfamily in health and disease. Several synthetic NR ligands are clinically used in the treatment of cancer, metabolic syndromes, inflammation, and immunosuppression. An emerging concept in the area of NR pharmacology is the principle of selective nuclear receptor modulators (SNRMs). SNRMs are NR ligands whose spectrum of activity can range from agonist to partial agonist to antagonist, in a tissue-selective manner. This phenomenon of tissue-selective action was first observed with the ER antagonist tamoxifen, which is widely used in the treatment and prevention of some forms of breast cancer. This chapter on NR targets presents an overview of the major steroid hormone and nonsteroid NRs, their physiological functions, their protein structures, natural and synthetic ligands, and their pharmacology and therapeutic applications, in the context of the tremendously active area of pharmaceutical drug discovery. The existing knowledge in this vast field is presented here in a manner that will allow the reader to understand the drug-discovery strategies in this area, so that this knowledge can be productively applied to the discovery of new targets and medications for the expanding class of oNRs that are waiting to be discovered.