Fish-hunting cone snail venoms are a rich source of minimized ligands of the vertebrate insulin receptor
Fish-hunting cone snail venoms are a rich source of minimized ligands of the vertebrate insulin receptor
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DOI：
10.7554/elife.41574
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发表时间：
2019-02-12
期刊：
影响因子：
7.7
通讯作者：
Safavi-Hemami, Helena
中科院分区：
文献类型：
--
作者：
Ahorukomeye, Peter;Disotuar, Maria M.;Safavi-Hemami, Helena
捕食鱼类的海锥蜗牛Conus geographus使用一种特殊的毒液胰岛素来诱导猎物低血糖休克。我们最近发现，这种毒液胰岛素，Con-Ins G1，具有与新胰岛素疗法设计相关的独特特征。在这里，我们表明，捕食鱼的锥体蜗牛提供了丰富的脊椎动物胰岛素受体的最小配体来源。地瓜、郁金香圆锥果和木芋圆锥果的胰岛素序列不同，但它们都能结合并激活人类胰岛素受体。分子动力学揭示了独特的作用模式，不同于自然界已知的任何其他胰岛素。当在斑马鱼和老鼠身上测试时，毒液胰岛素显著降低了链脲佐菌素诱导的糖尿病模型的血糖。我们的研究结果表明，锥螺已经进化出多种激活脊椎动物胰岛素受体的策略，并为设计治疗糖尿病的新药提供了独特的见解。
The fish-hunting marine cone snail Conus geographus uses a specialized venom insulin to induce hypoglycemic shock in its prey. We recently showed that this venom insulin, Con-Ins G1, has unique characteristics relevant to the design of new insulin therapeutics. Here, we show that fish-hunting cone snails provide a rich source of minimized ligands of the vertebrate insulin receptor. Insulins from C. geographus, Conus tulipa and Conus kinoshitai exhibit diverse sequences, yet all bind to and activate the human insulin receptor. Molecular dynamics reveal unique modes of action that are distinct from any other insulins known in nature. When tested in zebrafish and mice, venom insulins significantly lower blood glucose in the streptozotocin-induced model of diabetes. Our findings suggest that cone snails have evolved diverse strategies to activate the vertebrate insulin receptor and provide unique insight into the design of novel drugs for the treatment of diabetes.