THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: Nuclear hormone receptors (original) (raw)
Related papers
THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Nuclear hormone receptors
British Journal of Pharmacology, 2019
The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.14750\. Nuclear hormone receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, catalytic receptors, enzyme...
Nuclear Receptor Signaling, 2009
Nuclear hormone receptors (NHRs) represent a large and diverse family of ligand-activated transcription factors involved in regulating development, metabolic homeostasis, salt balance and reproductive health. The ligands for these receptors are typically small hydrophobic molecules such as steroid hormones, thyroid hormone, vitamin D3 and fatty acid derivatives. The first NHR structural information appeared ~20 years ago with the solution and crystal structures of the DNA binding domains and was followed by the structure of the agonist and antagonist bound ligand binding domains of different NHR members. Interestingly, in addition to these defined structural features, it has become clear that NHRs also possess significant structural plasticity. Thus, the dynamic structure of the NHRs was the topic of a recent stimulating and informative FASEB Summer Research Conference held in Vermont.
Nuclear receptors: from molecular mechanisms to therapeutics
Essays in Biochemistry
Nuclear receptors are classically defined as ligand-activated transcription factors that regulate key functions in reproduction, development, and physiology. Humans have 48 nuclear receptors, which when dysregulated are often linked to diseases. Because most nuclear receptors can be selectively activated or inactivated by small molecules, they are prominent therapeutic targets. The basic understanding of this family of transcription factors was accelerated in the 1980s upon the cloning of the first hormone receptors. During the next 20 years, a deep understanding of hormone signaling was achieved that has translated to numerous clinical applications, such as the development of standard-of-care endocrine therapies for hormonally driven breast and prostate cancers. A 2004 issue of this journal reviewed progress on elucidating the structures of nuclear receptors and their mechanisms of action. In the current issue, we focus on the broad application of new knowledge in this field for th...
Interactions of exogenous endocrine active substances with nuclear receptors
Pure and Applied Chemistry, 2003
Nuclear receptors function as ligand-regulated transcription factors and modulate the expression of sets of genes in response to varying concentrations of ligands. The ligand modulators can be endogenous metabolites that function as hormones, or they can be exogenous substances, such as pharmaceutical agents or environmental substances of natural or man-made origin, which in some cases can cause endocrine disruption. Ligands modulate nuclear receptor activity by binding to their ligand-binding domains and stabilizing conformations that lead either to transcriptional activation or repression. The ligand-binding pocket is somewhat flexible, and binding affinities can be measured over a 10-million-fold range (i.e., with equilibrium dissociation constant values ranging from ca. 0.01 nM to 100 µM). Thus, it is not surprising that by binding a large variety of structures, some nuclear receptors can appear to be promiscuous; however, when affinity is considered, the binding patterns are more restricted. The spectrum of ligands that bind to the estrogen receptor has been most thoroughly investigated. Those from natural sources include natural products in food, such as soy isoflavones and whole grain lignans, as well as microbial products and components from wood. Aside from pharmaceuticals, man-made estrogen ligands can be found in industrial products, such as alkyl phenols from nonionic detergents, bisphenols from plastics, indicator dye impurities, polymer chemicals, and chlorinated aromatics and pesticides. Exogenous ligands are also known for the androgen and progesterone receptors. While it is possible that endocrine disruption can result from exogenous chemicals acting directly as ligands for the nuclear receptors, endocrine disruption needs to be considered in the broader context; thus, compounds also need to be assessed for their effects at other levels, such as on endogenous hormone production, transport, metabolism, and clearance, and at points in signal transduction cascades that are beyond the ligand-receptor interaction.
Conserved functional motifs of the nuclear receptor superfamily as potential pharmacological targets
International Journal of Epigenetics, 2021
Nuclear receptors (NRs) are one of the most diverse and well-reported family of proteins. They are involved in numerous cellular processes as they play pivotal roles in cell signaling and the cell cycle. The participation of NRs in various applications in medicine and biology has greatly attracted the interest of the pharmaceutical industry for the discovery of novel and/or improved drugs for the treatment of several diseases, including cancer, diabetes or infertility. In the present study, in an effort to elucidate the molecular function of this superfamily and to identify novel pharmacological targets, a comprehensive sequence and structural analysis was performed using all available information from a repertoire of depositories. Functional conserved motifs were identified and analyzed with regards to their potential roles and implications in a number of biological processes. The essential differences among them were also addressed and discussed. In addition, these motifs were characterized in the main groups of the NRs, such as that of the steroid hormone receptors.
The Nuclear Receptor Resource: a growing family
Nucleic Acids Research, 1998
Last year, the original Glucocorticoid Receptor Resource expanded into a comprehensive project: the Nuclear Receptor Resource (NRR, http://nrr.georgetown.edu/nrr/ nrr.html ). The NRR has since been offering comprehensive information on nuclear receptor structure and function, as well as general facts of interest to the scientific community on meetings, funding and employment opportunities. The project now includes individual resources as part of a network which integrates information on glucocorticoid, androgen, mineralocorticoid, thyroid hormone, Vitamin D and peroxisome-proliferator activated receptors. Many investigators have joined the NRR network by filling out the Who is who? form available in the NRR home page. This has facilitated communication among scientists in the field and dissemination of data not otherwise published. Because several investigators have contacted NRR authors over the past few months asking for advice and materials for educational purposes, we have recently decided to include in our project an educational resource on nuclear receptors termed the 'Graphics Library'. The input and suggestions of NRR users do shape the future direction of the project, so we encourage users to continue to give us feedback.
Ligand-protein interactions in nuclear receptors of hormones
Nuclear hormone receptors are transcription factors regulated by lipophilic ligands. These hormones bind to their nuclear receptor targets using an induced fit mechanism that triggers a large conformational change and generates the proper surface for the binding of protein coactivators. The molecular details of the various steps of this activation process or its inhibition by antagonists are now understood for several nuclear receptors. ß
Sex, drugs and gene expression: signalling by members of the nuclear receptor superfamily
Essays in biochemistry, 2004
It is almost 20 years since the first steroid receptor cDNAs were cloned, a development that led to the concept of a superfamily of ligand-activated transcription factors: the nuclear receptors. Natural ligands for nuclear receptors are generally lipophilic in nature and include steroid hormones, bile acids, fatty acids, thyroid hormones, certain vitamins and prostaglandins. Nuclear receptors act principally to directly control patterns of gene expression and play vital roles during development and in the regulation of metabolic and reproductive functions in the adult organism. Since the original cloning experiments, considerable progress has been made in our understanding of the structure, mechanisms of action and biology of this important family of proteins.