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Team reveals extraordinary plasticity of the glucocorticoid receptor

The invention of the receptor’s structural versatility might contribute to the design of extra selective and fewer poisonous medicine for sufferers. Credit score: College of Barcelona

Glucocorticoids, comparable to cortisone, are among the many most generally used anti-inflammatory medicine, used to deal with bronchial asthma, psoriasis, organ transplantation, and even COVID-19. Relating to its pharmacological motion, the exercise of the glucocorticoid receptor (GR) is essential.

GR is a transcription issue that regulates important processes in human physiology. Nonetheless, the detailed three-dimensional construction of this nuclear receptor, one of the crucial essential therapeutic targets within the pharmaceutical business, stays an enigma for the scientific group.

Now, a examine revealed within the journal Nucleic Acid Analysis reveals for the primary time that GR is a extremely plastic protein with a extremely versatile construction: its monomers (constituent molecules) are able to self-assembling in several methods to type dimers, tetramers, and complexes with different proteins within the cell nucleus to regulate the expression of quite a few genes.

The invention of the hitherto unknown structural and practical versatility of GR and its molecular self-assembly course of (oligomerization) will contribute to the design of extra selective medicine with particular receptor conformations, in addition to much less poisonous to keep away from severe uncomfortable side effects than basic corticosteroids. generate in sufferers.

Keep away from uncomfortable side effects of glucocorticoids

The three-dimensional construction of the GR, which is important for its physiological exercise, has been questioned within the scientific literature. The primary construction of the GR ligand-binding area (GR-LBD) was revealed in 2002 within the journal Cell. In keeping with this mannequin, two GR-LBD molecules affiliate to type a dimer in a conformation by no means earlier than described in nuclear receptors.

These findings opened up a scientific debate, which nonetheless exists, in regards to the conformation of pink blood cells and their state of oligomerization in cells. Since pharmaceutical corporations have been inquisitive about growing medicine in opposition to GR, many of the subsequent structural research have centered on the interplay of GR-LBD with therapeutic compounds. In consequence, the evaluation of the oligomerization state of RBC was uncared for, producing a considerable amount of structural knowledge that was not examined intimately.

Analysis on the motion of glucocorticoids with out uncomfortable side effects has been based mostly solely on this partial mannequin of the dimerization state of GR. Historically, the GR, as soon as activated by corticosteroids, was thought-about to have the capability to carry out completely different capabilities within the cell relying on its oligomerization state: as a monomer it repressed pro-inflammatory genes, whereas as a dimer it might induce the expression of anti-inflammatory genes.

This dogma was challenged when the group on the NIH in Bethesda confirmed that GR might additionally act as a tetramer (4 GR molecules linked collectively, maybe a dimer of dimers) and have physiological exercise, whereas the monomeric type of the receptor didn’t regulate no operate. .

Nonetheless, the data that was recognized in regards to the construction of the GR couldn’t clarify how the receptor varieties these tetramers on the mobile degree. “Our work analyzes the oligomerization potential of GR-LBD and exhibits how this receptor can type as much as 20 completely different dimers. The outcomes recommend that a few of these dimers can affiliate to type practical tetramers when the receptor binds to DNA”, says Eva Estébanez, from the Division of Biochemistry and Molecular Biomedicine of the College of Biology.

The examine additionally recognized non-functional hexameric types of GR mutants which have been described in sufferers who don’t reply to corticosteroids (Chrousos syndrome or glucocorticoid resistance syndrome). “Subsequently, our examine associates for the primary time the formation of non-functional oligomers of GR (or of another nuclear receptor) with a uncommon human endocrinological illness of resistance to glucocorticoids”, says Estébanez.

An unknown structural plasticity in different nuclear receptors

To acquire the outcomes, the group has utilized a variety of strategies, from X-ray crystallography with synchrotron radiation (ALBA-CELLS) to the tactic generally known as Quantity and Brightness, a cutting-edge method in microscopy that permits visualizing the oligomerization state of the pink blood cells. in residing cells.

The examine has allowed researchers to clarify, from a structural standpoint, how GR dimers and tetramers could be fashioned, and the way the ligand-binding area is essential to those a number of conformations. The evaluation of all of the structural knowledge out there for the GRs, along with the brand new constructions resolved by the UB-IBUB group, has allowed them to find out a structural plasticity by no means seen earlier than in different nuclear receptors.

“This versatility permits the RBC to type dimers with completely different conformations that may be modulated, to a sure extent, relying on the kind of ligand that binds to the receptor, and this may clarify the power of the RBC to type tetramers,” says the researcher. Alba Jimenez.

“Our outcomes reinforce the info displaying the formation of energetic tetramers when the receptor binds to DNA and consolidate the speculation that the mechanism of motion of GRs in regulating transcription is far more complicated and versatile”, says the skilled. Andrea Alegre.

This multidisciplinary strategy has made it potential to switch the outcomes of the observations derived from the construction of proteins to the processes that happen on the mobile degree, a scientific advance with implications of curiosity in human physiology and within the battle in opposition to sure ailments.

Extra info:
Alba Jiménez-Panizo et al, The multivalence of the glucocorticoid receptor ligand-binding area explains its a number of physiological actions, Nucleic Acid Analysis (2022). DOI: 10.1093/nar/gkac1119

Supplied by the College of Barcelona

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