The insulin receptor (IR) is a type II receptor tyrosine kinase that plays essential roles in metabolism, growth, and proliferation. Dysregulation of IR signaling is linked to many human diseases, such as diabetes and cancers. The resolution revolution in cryo–electron microscopy has led to the determination of several structures of IR with different numbers of bound insulin molecules in recent years, which have tremendously improved our understanding of how IR is activated by insulin. Here, we review the insulin-induced activation mechanism of IR, including ( a) the detailed binding modes and functions of insulin at site 1 and site 2 and ( b) the insulin-induced structural transitions that are required for IR activation. We highlight several other key aspects of the activation and regulation of IR signaling and discuss the remaining gaps in our understanding of the IR activation mechanism and potential avenues of future research.

中文翻译：

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胰岛素受体的激活机制：结构视角

胰岛素受体 (IR) 是一种 II 型受体酪氨酸激酶，在代谢、生长和增殖中发挥重要作用。 IR 信号传导失调与许多人类疾病有关，例如糖尿病和癌症。近年来，冷冻电子显微镜的分辨率革命导致了多种具有不同数量结合胰岛素分子的IR结构的测定，这极大地提高了我们对胰岛素如何激活IR的理解。在这里，我们回顾了胰岛素诱导的IR激活机制，包括(a)胰岛素在位点1和位点2的详细结合模式和功能，以及(b)胰岛素诱导的IR激活所需的结构转变。我们重点介绍了 IR 信号传导激活和调节的其他几​​个关键方面，并讨论了我们对 IR 激活机制和未来研究潜在途径的理解中仍存在的差距。