Scholarlink

<p>Retinoic acid receptor-related orphan receptor γ (RORγ) is a member of the nuclear receptor superfamily involved in many physiological activities such as metabolic and autoimmune diseases, and therefore a potential therapeutic drug target. Here we report that the steroidal sapogenin, diosgenin, a novel ligand for RORγ, inhibits the transcriptional activity of the RORγ with distinctive properties in coregulator recruitment. Biochemical and cell-based studies indicated that diosgenin functions as a selective RORγ inverse agonist by inducing both coactivator and corepressor binding to RORγ, thereby uncovering a molecular mechanism for the actions of this natural compound. Further, the crystal structure of diosgenin complexed with the ligand-binding domain of RORγ reveals a unique binding mode including the active conformation of AF-2 helix and the conformational shift of Helix 11. Structural and functional studies suggest the plasticity of RORγ pockets in recognizing ligands and the vital roles of the backbone of diosgenin in recognizing RORγ. Our results provide a unique inverse agonist template of RORγ with high selectivity and efficacy, which contributes to further drug design and optimization targeting RORγ.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Structural basis for diosgenin as an inverse agonist of retinoic acid receptor-related orphan receptor γ

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月6日

查看全文
  • Shuming Chen,
  • Siyu Tian,
  • Junjie Liang,
  • Rui Wang,
  • Yong Li

摘要

Retinoic acid receptor-related orphan receptor γ (RORγ) is a member of the nuclear receptor superfamily involved in many physiological activities such as metabolic and autoimmune diseases, and therefore a potential therapeutic drug target. Here we report that the steroidal sapogenin, diosgenin, a novel ligand for RORγ, inhibits the transcriptional activity of the RORγ with distinctive properties in coregulator recruitment. Biochemical and cell-based studies indicated that diosgenin functions as a selective RORγ inverse agonist by inducing both coactivator and corepressor binding to RORγ, thereby uncovering a molecular mechanism for the actions of this natural compound. Further, the crystal structure of diosgenin complexed with the ligand-binding domain of RORγ reveals a unique binding mode including the active conformation of AF-2 helix and the conformational shift of Helix 11. Structural and functional studies suggest the plasticity of RORγ pockets in recognizing ligands and the vital roles of the backbone of diosgenin in recognizing RORγ. Our results provide a unique inverse agonist template of RORγ with high selectivity and efficacy, which contributes to further drug design and optimization targeting RORγ.