Nat. Struct. Mol. Biol. http://dx.doi.org/10.1038/nsmb.3292 (2016)

Credit: SACHIN RANADE

Despite their inoffensive appearance, marine cone snails are fearsome predators that can quickly subdue their prey with complex venoms. Whereas most venom components are neurotoxins that induce pain or paralysis, the venom of some fish-hunting snails has been found to contain peptides similar to fish insulins that can induce hypoglycemic shock in prey. One such venomous insulin (Con-Ins G1), produced by Conus geographus, is expressed as a monomer and lacks key residues responsible for hexamerization in vertebrate insulins. The residues missing in Con-Ins G1 are also critical for receptor engagement by vertebrate insulins. Menting et al. noted that this snail insulin is likely to retain the canonical disulfide-bonding pattern of vertebrate insulins, and they found that Con-Ins G1 strongly binds the human insulin receptor and activates signaling. A crystallographic analysis of Con-Ins G1 also revealed its three-dimentional structure and the stabilizing roles of specific post-translational modifications found to potentiate receptor activation. The structure was used to model Con-Ins G1's interaction with the human insulin receptor, which revealed how the small insulin could bind despite its lack of key structural elements present in its human counterpart. This could provide a basis for the future design of ultra-fast-acting insulins.