What Predatory marine cone snails use complex venoms to capture prey, including fish. We recently showed that Conus geographus, a snail whose stings are deadly to humans, uses an insulin to induce dangerously low blood sugar in its fish prey. Remarkably, we found that the venom insulin was much smaller than human insulin and that its small size allowed the rapid activation of the insulin receptor via a mechanism that had never been observed before. Following this important discovery, we have identified many more insulins from other fish hunting cone snails that are all diverse from each other and from the Conus geographus insulin. In this project, we will characterize the molecular and structural mode of action of the most diverse insulins identified from fish hunters to date. Why Insulin is one of the most important hormones and signaling molecules in nature. Our discovery of insulin in animal venom provided the first example of the use of insulin outside of its normal physiological function. Because of their streamlined role in predation, venom insulins act differently to our body’s own insulin that is used to maintain normal physiology. Therefore, venom insulins can teach us about new ways to activate the human insulin receptor. This information not only expands our understanding of the interaction between insulin and its receptor but also sheds light on how to make better molecular tools to study the various ways to activate the insulin receptor. How This project will utilize an interdisciplinary team and approach combining peptide chemistry and synthetic biology for venom insulin production, cell biology and pharmacology to study insulin receptor activation, and structural biology to visualize venom insulin-receptor interactions at high resolution. Briefly, venom insulins from ambush hunting cone snails will be generated using a combination of peptide chemistry and a new bacterial expression platform that we have optimized for the production of venom peptides, including insulins. Activity profiles will be comprehensively tested using receptor activation and signaling assays. We will then seek to determine the structures of the two-three most unusual venom insulins in complex with the human insulin receptor. SSR As scientists it is our social responsibility to serve as role models and give back to society. This will be achieved by Providing training to a graduate student and several undergraduate students working on this project. Communicating research outcomes to the public via news reports and podcasts. Publishing scientific outcomes in open-access journals. Providing novel molecular toolkits to the scientific community and the private sector.