Postech Biotech Center, Pohang University of Science and Technology (POSTECH), Pohang, 37673, Republic of Korea.
Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, 37673, Republic of Korea.
Exp Mol Med. 2023 Oct;55(10):2147-2161. doi: 10.1038/s12276-023-01101-1. Epub 2023 Oct 2.
The binding of insulin to the insulin receptor (IR) triggers a cascade of receptor conformational changes and autophosphorylation, leading to the activation of metabolic and mitogenic pathways. Recent advances in the structural and functional analyses of IR have revealed the conformations of the extracellular domains of the IR in inactive and fully activated states. However, the early activation mechanisms of this receptor remain poorly understood. The structures of partially activated IR in complex with aptamers provide clues for understanding the initial activation mechanism. In this review, we discuss the structural and functional features of IR complexed with various ligands and propose a model to explain the sequential activation mechanism. Moreover, we discuss the structures of IR complexed with biased agonists that selectively activate metabolic pathways and provide insights into the design of selective agonists and their clinical implications.
胰岛素与胰岛素受体（IR）的结合触发受体构象变化和自动磷酸化的级联反应，导致代谢和有丝分裂途径的激活。最近对 IR 的结构和功能分析的进展揭示了无活性和完全激活状态下 IR 的细胞外结构域构象。然而，这种受体的早期激活机制仍知之甚少。与适体结合的部分激活 IR 的结构为理解初始激活机制提供了线索。在这篇综述中，我们讨论了与各种配体结合的 IR 的结构和功能特征，并提出了一个解释顺序激活机制的模型。此外，我们还讨论了与选择性激活代谢途径的偏性激动剂结合的 IR 结构，为选择性激动剂的设计及其临床意义提供了见解。
