TY - JOUR TI - Fish-hunting cone snail venoms are a rich source of minimized ligands of the vertebrate insulin receptor AU - Ahorukomeye, Peter AU - Disotuar, Maria M AU - Gajewiak, Joanna AU - Karanth, Santhosh AU - Watkins, Maren AU - Robinson, Samuel D AU - Flórez Salcedo, Paula AU - Smith, Nicholas A AU - Smith, Brian J AU - Schlegel, Amnon AU - Forbes, Briony E AU - Olivera, Baldomero AU - Hung-Chieh Chou, Danny AU - Safavi-Hemami, Helena A2 - De Meyts, Pierre A2 - McCarthy, Mark I VL - 8 PY - 2019 DA - 2019/02/12 SP - e41574 C1 - eLife 2019;8:e41574 DO - 10.7554/eLife.41574 UR - https://doi.org/10.7554/eLife.41574 AB - 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. KW - cone snail KW - venom KW - insulin KW - hypoglycemic shock KW - prey capture KW - diabetes JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -