The signalling conformation of the insulin receptor ectodomain.,Nature Communications

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The signalling conformation of the insulin receptor ectodomain.
Nature Communications ( IF 14.7 ) Pub Date : 2018-10-24 , DOI: 10.1038/s41467-018-06826-6
Felix Weis ₁ , John G Menting ₂ , Mai B Margetts ₂ , Shu Jin Chan _{3,

4} , Yibin Xu _{2,

5} , Norbert Tennagels ₆ , Paulus Wohlfart ₆ , Thomas Langer ₆ , Christoph W Müller ₁ , Matthias K Dreyer ₆ , Michael C Lawrence _{2,

5}

Affiliation

Understanding the structural biology of the insulin receptor and how it signals is of key importance in the development of insulin analogs to treat diabetes. We report here a cryo-electron microscopy structure of a single insulin bound to a physiologically relevant, high-affinity version of the receptor ectodomain, the latter generated through attachment of C-terminal leucine zipper elements to overcome the conformational flexibility associated with ectodomain truncation. The resolution of the cryo-electron microscopy maps is 3.2 Å in the insulin-binding region and 4.2 Å in the membrane-proximal region. The structure reveals how the membrane proximal domains of the receptor come together to effect signalling and how insulin's negative cooperativity of binding likely arises. Our structure further provides insight into the high affinity of certain super-mitogenic insulins. Together, these findings provide a new platform for insulin analog investigation and design.

中文翻译：

胰岛素受体胞外域的信号传导构象。

了解胰岛素受体的结构生物学及其信号传导方式对于开发治疗糖尿病的胰岛素类似物至关重要。我们在这里报道了与生理相关的高亲和力版本的受体胞外域结合的单个胰岛素的冷冻电子显微镜结构，后者是通过连接C端亮氨酸拉链元件产生的，以克服与胞外域截断相关的构象灵活性。冷冻电镜图的分辨率在胰岛素结合区域为 3.2 Å，在膜近端区域为 4.2 Å。该结构揭示了受体的膜近端结构域如何聚集在一起以影响信号传导，以及胰岛素的负协同结合如何可能出现。我们的结构进一步深入了解某些超促有丝分裂胰岛素的高亲和力。总之，这些发现为胰岛素类似物的研究和设计提供了一个新平台。

更新日期：2018-10-24

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