Dalle Molle Institute for Artificial Intelligence USI-SUPSI Polo universitario Lugano - Campus Est, Via la Santa 1, 6962, Lugano-Viganello, Switzerland.
AO Research Institute Davos, Clavadelerstrasse 8, 7270, Davos Platz, Switzerland.
J Mol Graph Model. 2023 Dec;125:108587. doi: 10.1016/j.jmgm.2023.108587. Epub 2023 Aug 4.
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.
糖皮质激素受体（GR）是一种核受体，通过调节特定基因的转录来控制关键的生物过程。GR 的转录活性受一系列配体和辅酶的调节，其中配体可以作为激动剂或拮抗剂。GR 激动剂，如糖皮质激素地塞米松（DEX）和泼尼松龙，被广泛用于治疗炎症和自身免疫性疾病患者。DEX 也被用于体外诱导成骨分化。最近，DEX 通过下调转录因子性盒转录因子 9（SOX9）和上调过氧化物酶体增殖物激活受体 γ（PPARG）来诱导人间充质基质细胞成骨分化的变化，这一点受到了关注。SOX9 在控制软骨生成中起着重要作用，但也通过作为 RUNX2 的显性负调控因子在成骨中起作用。在细胞命运决定过程中，许多过程仍有待阐明，例如关键转录因子之间的相互作用。这项工作的主要目的是使用分子动力学模拟在原子分辨率水平上阐明在存在和不存在 DEX 的情况下 GR 和 SOX9 之间的相互作用。这项研究的结果可以帮助理解 GR 和 SOX9 之间可能的分子相互作用及其在决定细胞命运中的作用。结果突出了 GR 和 SOX9 之间复合物形成过程中涉及的关键残基，并阐明了 DEX 调节 GR-SOX9 结合并发挥其生物学活性的机制。
