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Cryo-EM structure of the complete and ligand-saturated insulin receptor ectodomain
Journal of Cell Biology ( IF 7.4 ) Pub Date : 2019-11-14 , DOI: 10.1083/jcb.201907210
Theresia Gutmann 1, 2 , Ingmar B Schäfer 3 , Chetan Poojari 4 , Beate Brankatschk 1, 2 , Ilpo Vattulainen 4, 5 , Mike Strauss 6 , Ünal Coskun 1, 2
Affiliation  

Glucose homeostasis and growth essentially depend on the hormone insulin engaging its receptor. Despite biochemical and structural advances, a fundamental contradiction has persisted in the current understanding of insulin ligand–receptor interactions. While biochemistry predicts two distinct insulin binding sites, 1 and 2, recent structural analyses have resolved only site 1. Using a combined approach of cryo-EM and atomistic molecular dynamics simulation, we present the structure of the entire dimeric insulin receptor ectodomain saturated with four insulin molecules. Complementing the previously described insulin–site 1 interaction, we present the first view of insulin bound to the discrete insulin receptor site 2. Insulin binding stabilizes the receptor ectodomain in a T-shaped conformation wherein the membrane-proximal domains converge and contact each other. These findings expand the current models of insulin binding to its receptor and of its regulation. In summary, we provide the structural basis for a comprehensive description of ligand–receptor interactions that ultimately will inform new approaches to structure-based drug design.

中文翻译:

完整且配体饱和的胰岛素受体胞外域的冷冻电镜结构

葡萄糖稳态和生长基本上取决于激素胰岛素与其受体的结合。尽管生化和结构方面取得了进展,但目前对胰岛素配体-受体相互作用的理解仍然存在一个基本矛盾。虽然生物化学预测了两个不同的胰岛素结合位点 1 和 2,但最近的结构分析仅解析了位点 1。利用冷冻电镜和原子分子动力学模拟的组合方法,我们提出了用四个饱和的整个二聚胰岛素受体胞外域的结构。胰岛素分子。作为对先前描述的胰岛素-位点 1 相互作用的补充,我们提出了胰岛素与离散胰岛素受体位点 2 结合的第一个视图。胰岛素结合使受体胞外域稳定在 T 形构象中,其中膜近端域会聚并相互接触。这些发现扩展了当前胰岛素与其受体结合及其调节的模型。总之,我们为配体-受体相互作用的全面描述提供了结构基础,最终将为基于结构的药物设计新方法提供信息。
更新日期:2019-11-14
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