Family reunion of nuclear hormone receptors: structures, diseases, and drug discovery

Abstract

EditorialHormones comprise one of the most effective classes of messengers that transmit cell to cell communication in eukaryotic systems. Cells receive messages of hormones through protein receptors, and then translate the hormone signals into concrete action of physiological responses. Homeostasis of hormone systems is essential for human health, and aberrant regulation of hormone signaling has been associated with many diseases, including cancer, diabetes, and inflammation diseases. As such, targeting hormone signaling pathways has become a major venue of pharmacological intervention of many health abnormalities. There are two major classes of hormone receptors: G-protein coupled receptors and nuclear hormone receptors, both of which consist of the top two classes of the most successful drug targets. Two years ago, we published a special issue on structures, biology and drug discovery of G-protein coupled receptors, which has been well received by drug discovery research communities. This year marked the 30th anniversary of the cloning of the first member of the nuclear receptor family and 25th year of the discovery of orphan nuclear receptors, for which no cognate ligands were known at the time of their cloning. Since then we have witnessed a tremendous expansion of our knowledge of this family of receptors. In this special issue, we collected eleven exciting review articles, highlighting our current understanding of structure, function, disease relevance, and drug discovery of nuclear receptors.Hormones androgen and estrogen have long been known to play key roles in development, growth, and homeostasis of reproductive systems and their dysregulation is the major cause of prostate cancer and breast cancer. The first article by Tan and coworkers will provide comprehensive review on structures, diseases relevance and drug discovery of androgen receptor, the oncogenic driver of prostate cancer [1] . The second review article by Ikeda and coworkers covers the roles of estrogen-responsive genes in breast cancer [2] . Beside androgen receptor and estrogen receptor, the two of classical steroid hormone receptors in cancers, orphan nuclear receptors COUPTFs also known to play important role in tumorigenesis, and they are respectively reviewed by Xu and coworkers [3] . In addition, the roles of bile acid receptor FXR in liver cancer will be reviewed by Huang and coworkers [4] . Nuclear hormone receptors are also well known for their central roles in metabolic regulation. Classic examples are peroxisome proliferator activated receptors (PPARs) and receptors for glucocorticoids and thyroid hormone, for which roles have been well reviewed in the literatures. In this special issue, we will focus on the emerging roles of orphan nuclear receptors in metabolism. Jiao and coworkers review the regulatory role of FXR in homeostasis of hepatic triglyceride [5] . Audet-wash and Giguère review the roles of estrogen-related receptor α and γ in metabolic control and related diseases [6] . Yan and Xie review the role of constitutive...

The orphan G protein-coupled receptor GPR139 is activated by the peptides: Adrenocorticotropic hormone (ACTH), α-, and β-melanocyte stimulating hormone (α-MSH, and β-MSH), and the conserved core motif HFRW

“…1). GPR139 has been shown to signal trough Gα s (Hu et al., 2009), Gα i (Süsens et al., 2006) and Gα q (Dvorak et al., 2015, Isberg et al., 2014, Liu et al., 2015, Matsuo et al., 2005, Shehata et al., 2016, Shi et al., 2011, Wang et al., 2015), however in CHO-k1 cells GPR139 only signals via the Gα q -coupled signaling pathway (Isberg et al., 2014, Shehata et al., 2016). The main signaling pathway of MC4R is through Gα s (reviewed in (Tao, 2010)).…”

The nuclear receptor superfamily: A structural perspective

“…Our knowledge of the NR family has drastically expanded within the last decade due to advancements in genome‐wide methodologies, structural studies of receptor domains and full‐length complexes, and identification of new co‐regulator proteins that modulate receptor activity . This work has laid the foundation for pharmaceutical companies and academic researchers to develop synthetic ligands that target these receptors . Yet, due to the diverse array of genes regulated by these proteins, along with the fact that many drugs are not explicitly specific for one receptor, drugs that target NRs tend to have unwanted side effects .…”

“…This work has laid the foundation for pharmaceutical companies and academic researchers to develop synthetic ligands that target these receptors . Yet, due to the diverse array of genes regulated by these proteins, along with the fact that many drugs are not explicitly specific for one receptor, drugs that target NRs tend to have unwanted side effects . For this reason, more research is required to understand all the mechanisms that guide NR regulation.…”