The glucocorticoid receptor (GR) plays a crucial role in medicine, particularly in the treatment of inflammatory and autoimmune diseases. Glucocorticoids are a class of steroid hormones that are synthesized and released by the adrenal glands, and they act by binding to the GR to regulate gene expression and control a variety of physiological processes, including metabolism, immune response, and stress response. The GR is expressed in almost every cell type in the body, and its activation by glucocorticoids can have both beneficial and detrimental effects on human health. On the one hand, glucocorticoids are potent anti-inflammatory and immunosuppressive agents that can effectively treat a wide range of diseases, including rheumatoid arthritis, asthma, inflammatory bowel disease, and multiple sclerosis. They can also be used to prevent rejection of transplanted organs and to reduce inflammation following surgery or injury.
On the other hand, long-term use of glucocorticoids can lead to a host of adverse effects, including osteoporosis, hypertension, hyperglycemia, weight gain, muscle wasting, and increased susceptibility to infections. These side effects are thought to be due to the non-specific nature of glucocorticoid therapy, which can activate the GR in a variety of tissues and cell types throughout the body.
Recent advances in our understanding of the structural and functional properties of the GR have led to the development of new drugs that target the receptor with greater specificity and selectivity. These drugs aim to retain the anti-inflammatory and immunosuppressive properties of glucocorticoids while minimizing their side effects.
For example, selective glucocorticoid receptor agonists (SEGRAs) are a class of drugs that are designed to selectively activate the GR in specific tissues or cell types, thereby reducing the risk of systemic side effects. These drugs have shown promise in preclinical studies for the treatment of inflammatory and autoimmune diseases, as well as for the prevention of chemotherapy-induced nausea and vomiting.
Other approaches to targeting the GR include modulating its interactions with co-regulatory proteins and developing drugs that can stabilize specific GR conformations. These strategies hold great potential for the development of new and improved glucocorticoid therapies that can effectively treat inflammatory and autoimmune diseases while minimizing their side effects.
The glucocorticoid receptor plays a critical role in human physiology and medicine, and advances in our understanding of its structure and function have opened up new avenues for the development of safer and more effective glucocorticoid therapies. By targeting the GR with greater specificity and selectivity, we can harness the anti-inflammatory and immunosuppressive properties of glucocorticoids while minimizing their adverse effects, and ultimately improve the health and well-being of millions of patients worldwide. A new study recently published in the scientific journal Nucleic Acids Research has discovered a previously unknown structural and functional versatility in the glucocorticoid receptor (GR), a protein responsible for controlling the expression of numerous genes in the cell nucleus. The study has revealed that the GR is a highly plastic protein with a highly versatile structure, capable of self-assembling in different ways to form dimers, tetramers, and complexes with other proteins. This discovery of the molecular self-assembly process or oligomerization of the GR has significant implications for the development of drugs that are more selective and less toxic in order to avoid the serious side effects of classical corticosteroids.
The three-dimensional structure of the GR has been essential for its physiological activity, but it has been questioned in the scientific literature. The first structure of the GR ligand-binding domain (GR-LBD) was published in 2002, which showed that two GR-LBD molecules associate to form a dimer in a conformation never before described in nuclear receptors. However, subsequent structural studies focused more on the interaction of the GR-LBD with therapeutic compounds, neglecting the analysis of the oligomerization state of the GR.
Research on glucocorticoid action without side effects has been based exclusively on a partial model of the GR dimerization state. It was traditionally believed that the GR could perform different functions in the cell depending on its oligomerization state: as a monomer, it repressed pro-inflammatory genes, while as a dimer, it could induce the expression of anti-inflammatory genes. However, the NIH team in Bethesda challenged this dogma and showed that the GR could also act as a tetramer and have physiological activity.
The study published in Nucleic Acids Research has now explained how the receptor forms these tetramers at the cellular level. It analyzes the oligomerization potential of GR-LBD and shows how this receptor can form up to 20 different dimers, some of which can associate to form functional tetramers when the receptor binds to DNA. The study has also identified non-functional hexameric forms of GR mutants that have been described in patients who do not respond to corticosteroids.
The team used a wide range of techniques, from X-ray crystallography with synchrotron radiation to the method known as Number and Brightness, a leading microscopy technique that allows visualization of the oligomerization state of GRs in living cells. The study has allowed the researchers to determine a structural plasticity never seen before in other nuclear receptors.
The structural plasticity of the GR allows it to form dimers with different conformations that can be modulated depending on the type of ligand that binds to the receptor. This would explain the ability of the GR to form tetramers. The results reinforce the data showing the formation of active tetramers when the receptor binds to DNA, and consolidate the hypothesis that the mechanism of action of the GR in the regulation of transcription is much more complex and versatile.
The multidisciplinary approach used in this study has made it possible to transfer the results from observations derived from protein structure to processes occurring at the cellular level, a scientific progress with implications of interest in human physiology and the fight against certain diseases. The discovery of the molecular self-assembly process or oligomerization of the GR has significant implications for the development of drugs that are more selective and less toxic in order to avoid the serious side effects of classical corticosteroids. The study has also associated the formation of non-functional oligomers of GR to a rare human endocrinological disease of glucocorticoid resistance.
Alba Jiménez-Panizo, Andrea Alegre-Martí, Theophilus T Tettey, Gregory Fettweis, Montserrat Abella, Rosa Antón, Thomas A Johnson, Sohyoung Kim, R Louis Schiltz, Israel Núñez-Barrios, Joan Font-Díaz, Carme Caelles, Annabel F Valledor, Paloma Pérez, Ana M Rojas, Juan Fernández-Recio, Diego M Presman, Gordon L Hager, Pablo Fuentes-Prior, Eva Estébanez-Perpiñá, The multivalency of the glucocorticoid receptor ligand-binding domain explains its manifold physiological activities, Nucleic Acids Research, Volume 50, Issue 22, 9 December 2022, Pages 13063–13082, https://doi.org/10.1093/nar/gkac1119