The molecular mechanism that governs how the glucocorticoid receptor (GR) assembles into higher-order structures inside the cell, a process fundamental to how the receptor regulates gene expression, immune responses, and metabolism, has been uncovered by researchers at the Institute of Biomedicine (IBUB) of the University of Barcelona. The study, published in Nucleic Acids Research, shows that the GR forms tetramers, not just monomers or dimers as previously believed, unlocking a new, potentially fertile, ground for the development of new therapies for a range of conditions.
“The glucocorticoid receptor controls approximately 20% of the human transcriptome and is fundamental in the regulation of glycemia, metabolism and the anti-inflammatory response,” said senior author Eva Estébanez-Perpiñá, PhD, a professor and principal investigator at the University of Barcelona. “This is, in fact, the first time that we present to the scientific community a coherent mechanism to explain how the GR associates within the cell nucleus.”
Drugs targeting the GR are widely used to treat autoimmune and inflammatory diseases such as asthma, psoriasis, and rheumatoid arthritis. Current drugs, however, can produce significant side effects such as immunosuppression and bone loss. The new findings suggest that the receptor’s ability to form different multimeric assemblies, tetramers in particular, plays a central role in determining how a person responds to current drugs. This new understanding will now allow research to design a new generation of glucocorticoid drugs that could minimize adverse drug reactions.
The glucocorticoid receptor (also known as NR3C1) is expressed in nearly all human cells and acts as a ligand-activated transcription factor. Once bound to glucocorticoid hormones, it regulates thousands of genes involved in stress responses, immune modulation, and metabolism.
“The glucocorticoid receptor (GR) is a leading drug target due to its anti-inflammatory and immunosuppressive roles. The functional oligomeric conformation of full-length GR (FL-GR), which is key for its biological activity, remains disputed,” the researchers wrote. “Here we present a new crystal structure of agonist-bound GR ligand-binding domain (GR-LBD) comprising eight copies of a noncanonical dimer.” This data revealed how small structural motifs in the ligand-binding domain, especially within loops and helices, mediate the assembly of GR dimers into tetramers that anchor to DNA and regulate gene transcription.
For decades, scientists worked with the belief that the GR functioned either as a single molecule or a homodimer. “The GR’s active conformation is clearly different from the traditional model that has been described for other nuclear receptors,” said co-author Pablo Fuentes-Prior, PhD, a researcher at IBUB. “This confirms that the GR functions differently from its homologues.”
To conduct their investigation, the team combined the use of X-ray crystallography, molecular dynamics simulations, crosslinking mass spectrometry, fluorescence microscopy, and transcriptomic analysis to study living cells.
“This combined strategy was essential to overcome the difficulties inherent in studying such a structurally complex protein,” the researchers wrote. “Thanks to this, we have been able to propose a detailed and coherent molecular mechanism for the interactions that drive glucocorticoid receptor multimerization.”
Mutations that alter GR multimerization have direct implications for human disease. In Chrousos syndrome, or generalized glucocorticoid resistance, genetic variants disrupt the receptor’s assembly process, producing dysfunctional oligomers. The study provides the first detailed explanation for how surface residue mutations, which were previously classified as mutations of unknown significance, can increase the receptor’s hydrophobicity, promoting formation of larger, less active complexes such as hexamers or octamers. Such altered forms compromise normal GR signaling, leading to metabolic and immune dysregulation.
Prior research by this same group laid the foundation for this discovery. In 2022, the team mapped the multiple modes of GR dimerization and identified key interfaces within the ligand-binding domain. That earlier work raised questions, however, about which forms were biologically relevant, which led them to the current research.
The broad physiological effects of GR are well known. It regulates inflammation, metabolism, glucose homeostasis, and stress responses across nearly every tissue type. Because of this, any imbalance in its signaling can produce wide-ranging effects, from immune suppression to metabolic disorders. By revealing how the receptor’s structure determines its function, the study provides a molecular-level information that can guide new drug discovery efforts.
Looking ahead, the researchers plan to investigate how different DNA sequences and co-regulator proteins influence GR multimerization and how specific disease-linked mutations reshape this structural landscape. Future studies will also explore whether distinct tetrameric assemblies correspond to unique gene programs or chromatin contexts, with potential implications for personalized glucocorticoid therapies.
“Apart from autoimmune and inflammatory diseases, these findings open new avenues to address diseases associated with GR dysfunction, including asthma, Cushing’s syndrome and Addison’s disease,” the researchers noted. “Ultimately, our research lays the foundation for the design of precision drugs capable of modulating GR function with unprecedented specificity.”
