Li Wenchao, Dao Yuankun, Lin Terra, Austin Maxwell J, Lin Nai-Pin, Chou Danny Hung-Chieh
Department of Pediatrics, Division of Diabetes and Endocrinology, Stanford University, USA.
Department of Chemistry, Stanford University, USA.
Org Biomol Chem. 2025 May 14;23(19):4776-4781. doi: 10.1039/d5ob00363f.
Insulin receptor (IR) activation requires coordinated engagement of two distinct insulin-binding sites, and recent structural insights have highlighted the role of a disulfide bond in IR agonist S597 in the S597-IR complex. In this study, we synthesized and evaluated analogs of S597 and the IR antagonist Ins-AC-S2, replacing their native disulfide bridges with alternative linkages. While these modifications had minimal impact on Ins-AC-S2's antagonistic activity, they significantly reduced the agonistic potency of S597, suggesting that conformational stability is critical for receptor activation. Our findings provide a structural basis for designing non-insulin ligands to selectively activate or inhibit the insulin receptor, with potential therapeutic implications.
胰岛素受体（IR）的激活需要两个不同的胰岛素结合位点协同作用，最近的结构研究突出了S597-IR复合物中IR激动剂S597中二硫键的作用。在本研究中，我们合成并评估了S597和IR拮抗剂Ins-AC-S2的类似物，用替代连接取代它们天然的二硫键。虽然这些修饰对Ins-AC-S2的拮抗活性影响最小，但它们显著降低了S597的激动效力，表明构象稳定性对受体激活至关重要。我们的研究结果为设计非胰岛素配体以选择性激活或抑制胰岛素受体提供了结构基础，具有潜在的治疗意义。
