Fast Acting Insulins from Fish-Hunting Cone Snail Venom
Insulins in the venom of certain fish-hunting cone snails facilitate prey capture by rapidly inducing hypoglycemic shock. One such insulin, Conus geographus G1 (Con-Ins G1), is the smallest known insulin found in nature and lacks the C-terminal segment of the B chain that, in human insulin (hIns), mediates engagement of the insulin receptor and assembly of the hormone’s hexameric storage form. Removal of this segment (residues B23–B30) in human insulin results in substantial loss (< 0.1%) of receptor affinity. Menting, et al. (http://www.nature.com/nsmb/journal/v23/n10/full/nsmb.3292.html) found that Con-Ins G1 is monomeric, strongly binds the human insulin receptor and activates receptor signaling. Con-Ins G1 thus is a naturally occurring B-chain-minimized mimetic of human insulin. The crystal structure of Con-Ins G1 reveals a tertiary structure highly similar to that of human insulin. These findings are intriguing in that they indicate that Con-Ins G1 contains a structural element that mitigates the lack of an equivalent to the critical hIns residue PheB24. The crystal structure of Con-Ins G1 coupled with molecular modeling suggests that this element is formed by the tyrosine residues at position B15 and possibly also B20, whose side chains then act as surrogates for the key receptor-engaging residue PheB24 in hIns. These structural findings provide a platform for the design of a novel class of therapeutic human insulin analogs that are intrinsically monomeric and rapid acting and indicates how Con-Ins G1’s lack of an equivalent to the key receptor-engaging residue PheB24 is mitigated. Their findings on Con-Ins-G1 may facilitate efforts to design ultrarapid-acting therapeutic insulins.