Extraordinary plasticity of glucocorticoid receptors!

Corticosteroids (such as cortisone) are one of the most widely used anti-inflammatory drugs and are used to treat asthma, psoriasis, organ transplants, and even COVID-19
.
In connection with its pharmacological action, the activity of glucocorticoid receptor (GR) is crucial
.
GR is a transcription factor that regulates important processes
in human physiology.
However, the detailed three-dimensional structure of this nuclear receptor, one of the most important therapeutic targets in the pharmaceutical industry, remains a mystery
to the scientific community.

Now, a study published in the journal Nucleic Acid Research reveals for the first time that GR is a highly plasticizable protein with a highly versatile structure: its monomers (constituent molecules) are able to self-assemble in different ways, forming dimers, tetramers, and complexes with other proteins in the nucleus to control the expression
of numerous genes.

The discovery of previously unknown structural and functional versatility of GR and its molecular self-assembly process (oligomerization) will help to design drugs that are more selective for specific conformations of receptors, as well as lower toxicity, to avoid the serious side effects
that classical corticosteroids produce in patients.

Avoid side effects of glucocorticoids

The three-dimensional structure of GRs is essential for their physiological activity, but has been questioned
in the scientific literature.
The first structure of the GR ligand binding domain (GR-lbd) was published in the journal Cell in 2002.
According to this model, two GR-LBD molecules combine to form a dimer whose conformation has never been described in nuclear
receptors.

These findings opened a scientific debate about the conformation of red blood cells and their oligomerization state in cells, which is still ongoing
today.
Since pharmaceutical companies have been keen to develop drugs against GR, most subsequent structural studies have focused on the interaction of GR-lbd with therapeutic compounds
.
As a result, the analysis of the oligomeric state of RBCs is ignored, resulting in a large amount of structural data that is still not examined
in detail.

Studies of the non-side-effect effects of glucocorticoids are based entirely on this partial model
of GR dimers.
Traditionally, GR, once activated by corticosteroids, is thought to have the ability to perform different functions in cells, depending on its oligomeric state: as a monomer, it can inhibit pro-inflammatory genes, while as a dimer, it can induce the expression
of anti-inflammatory genes.

This theory was challenged when the Bethesda-based NIH team showed that GR could also act as a tetramer (four GR molecules linked together, possibly a dimer within a dimer) and be physiologically active, while the monomeric form of the receptor did not regulate any function
.

However, known GR structural information does not explain how receptors form these tetramers
at the cellular level.
"Our work analyzes the oligomeric potential of GR-LBD and shows how this receptor can form up to 20 different dimers
.
The results show that when the receptor binds to DNA, some of these dimers can combine to form functional tetramers", says
Eva Estébanez from the Department of Biochemistry and Molecular Biomedical Sciences in the Faculty of Biology.

The study also found non-functional hexameric forms
of GR mutants described in patients who did not respond to corticosteroids (Chroseos syndrome or glucocorticoid resistance syndrome).
"Thus, for the first time, our study links the formation of non-functional oligomers of GR (or any other nuclear receptor) to a rare glucocorticoid-resistant endocrine disease
," said Estébanez.

Unknown structural plasticity in other nuclear receptors

To obtain the results, the team applied a wide range of techniques, from synchrotron radiation X-ray crystallography (ALBA-CELLS) to a method known as "quantity and brightness," a leading microscopy technique that visualizes the oligomeric state
of RBCs in living cells.

This study allowed the researchers to explain structurally how GR dimers and tetramers are formed and how ligand binding domains are key
to these multi-remodeling images.
The analysis of all the structural data available to GR, along with the new structure addressed by the UB-IBUB group, allowed them to determine structural plasticity never seen in other nuclear receptors
.

"This versatility allows RBCs to form dimers with different conformations, in part depending on the type of ligand bound to the receptor, which could explain RBC's ability to
form tetramers," said researcher Alba Jiménez.
"

Expert Andrea Alegre said: "Our results strengthen the data showing the formation of active tetramers when receptors bind to DNA and reinforce the hypothesis
that the mechanism of action of GR in transcriptional regulation is more complex and multifunctional.
"

This multidisciplinary approach makes it possible to transfer observations obtained from protein structures to processes that occur at the cellular level, a scientific advance with important implications
for human physiology and the fight against certain diseases.