Influence of Dexamethasone on the Interaction Between Glucocorticoid Receptor and SOX9: a Molecular Dynamics Study


Stojceski, Filip (Dalle Molle Institute for Artificial Intelligence (IDSIA-SUPSI-USI) )



The glucocorticoid receptor (GR) is a nuclear receptor that controls critical biological processes by regulating the transcription of specific genes. GR transcriptional activity is modulated by a series of ligand and coenzymes, where a ligand can act as an agonist or antagonist. GR agonists, such as the glucocorticoids dexamethasone (DEX) and prednisolone, are widely prescribed to patients with inflammatory and autoimmune diseases. DEX is also used to induce osteogenic differentiation in vitro. Recently, we highlighted that DEX induces changes in osteogenic differentiation of human mesenchymal stromal cells by inhibiting the transcription factor SRY-box transcription factor 9 (SOX9) and upregulating the peroxisome proliferator activated receptor γ (PPARG) [1]. SOX9 is fundamental in the control of chondrogenesis, but also in osteogenesis by acting as a dominant negative of RUNX2. There are still many processes to be clarified during cell fate determination, such as the interplay between the key transcription factors. The main objective pursued by this work is to shed light on the interaction between GR and SOX9 in presence and in absence of DEX at an atomic level of resolution using molecular dynamics (MD) simulations. The outcome of this work could help the understanding of possible molecular interactions between GR and SOX9 and their role on the determination of cell fate. Moreover, the impact of DEX on the previously mentioned macro molecular interactions will be fully clarified.


Classical MD has been used to perform a systematic investigation of a series of docked pose between GR, with and without DEX, and SOX9. HDOCK web server was used to obtain the initial docked configuration, considering as docking target for SOX9 the GR’s dimerization and coenzyme moieties. All the SOX9-GR initial docked configuration were simulated in presence and in absence of DEX complexed with GR. The AMBER99SB-ILDN force field and TIP3P water molecules was used for defining system topology.


The results showed that DEX has an influence on the binding behavior between SOX9 and GR. The SOX9 protein docked within the GR’s coenzyme moiety showed a different binding behavior depending on the presence or absence of DEX bound to the GR’s ligand binding domain. It is worth mentioning that when DEX is absent from the GR, SOX9 has the capability to strongly interact with the GR’s coenzyme domain. Contrariwise, when DEX is bound, SOX9 has impaired capability to interact with the GR’s coenzyme domain. Finally, no significant difference has been observed in the simulations of SOX9 docked the GR’s dimerization domain, with and without DEX complexed to GR.


This work sheds light on the modulator effect carried out by DEX on the interaction between GR and SOX9. The fruitful information extracted from this study may help the understanding at molecular level of the interaction between the nuclear receptor GR and SOX9 in the presence or absence of DEX, which can prompt a better understanding of the entire osteogenic differentiation pathway of human mesenchymal stromal cells.

[1] Della Bella E. et al. (2021) Int J Mol Sci 22 (9):4785.


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