Details

Autor(en) / Beteiligte

• Stojceski, Filip
• Buetti-Dinh, Antoine
• Stoddart, Martin J.
• Danani, Andrea
• Della Bella, Elena
• Grasso, Gianvito

Titel

Influence of dexamethasone on the interaction between glucocorticoid receptor and SOX9: A molecular dynamics study

Ist Teil von

• Journal of molecular graphics & modelling, 2023-12, Vol.125, p.108587-108587, Article 108587

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2023

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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 ligands 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, it has been highlighted that DEX induces changes in the osteogenic differentiation of human mesenchymal stromal cells by downregulating the transcription factor SRY-box transcription factor 9 (SOX9) and upregulating the peroxisome proliferator-activated receptor γ (PPARG). SOX9 is fundamental in the control of chondrogenesis, but also in osteogenesis by acting as a dominant-negative of RUNX2. Many processes remain 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 the presence and absence of DEX at an atomic level of resolution using molecular dynamics simulations. The outcome of this research could help the understanding of possible molecular interactions between GR and SOX9 and their role in the determination of cell fate. The results highlight the key residues at the interface between GR and SOX9 involved in the complexation process and shed light on the mechanism through which DEX modulates GR-SOX9 binding and exerts its biological activity. [Display omitted] •This study systematically investigates the interaction between the glucocorticoid receptor (GR) and SOX9, examining the effects of Dexamethasone (DEX) on this interaction.•The results demonstrate that DEX enhances the interaction between GR and SOX9, leading to a more stable complex formation.•The presence of DEX is associated with increased total buried surface and hydrogen bond formations between GR's coenzyme binding domain (CBD) and SOX9.•Stronger GR-SOX9 interaction with DEX hints at how DEX modulates SOX9 activity, affecting osteogenic differentiation.