Drugs to treat inflammatory and autoimmune diseases - such as asthma, psoriasis, rheumatoid arthritis or Chrousos syndrome - act mainly through the glucocorticoid receptor (GR). This essential protein regulates vital processes in various tissues, so understanding its structure and function at the molecular level is essential for designing more effective and safer drugs. Now, a study published in the journal Nucleic Acids Research ( NAR ) has revealed the mechanism of multimerization - the association of different molecules to form complex structures - of the glucocorticoid receptor, a process critical to its physiological function.
Deciphering how the GR forms oligomers - through the binding of several subunits - opens a crucial avenue for developing more selective drugs. These new drugs could modulate this association and thus minimize serious adverse effects, such as immunosuppression or bone loss.
The study was led by researcher Eva Estébanez-Perpiñá, Serra Húnter professor at the Department of Biochemistry and Molecular Biomedicine at the Faculty of Biology and the Institute of Biomedicine (IBUB) of the University of Barcelona, based at the Barcelona Science Park (PCB). Young researchers Andrea Alegre-Martí and Alba Jiménez-Paniño (IBUB) are the first co-authors of the paper.
The study, which stands out for its multidisciplinary perspective, is the result of an extensive national and international collaboration that has brought together teams led by Gordon L. Hager, from the US National Institutes of Health (NIH), and Jaime Rubio and M. Núria Peralta, from the UB's Faculty of Chemistry and the Institute of Theoretical and Computational Chemistry (IQTCUB), as well as members of the Mass Spectrometry and Proteomics core facility at the Institute for Research in Biomedicine (IRB Barcelona), the Research Centre of Vine and Wine Related Science (ICVV-CSIC), the Institute of Biomedicine of Valencia (IBV-CSIC) and the University of Buenos Aires (Argentina).
A flexible protein with multiple conformations
For decades, the scientific community had considered that the GR acted only as a monomer or as a homodimer (i.e. one or two copies of the receptor). This study breaks from the traditional model and reveals, for the first time, that inside the cell nucleus the receptor forms larger oligomers, mainly composed of four subunits (tetramers).
