5jyq
Structure of Conus Geographus insulin G1
Structural highlights
FunctionINS1A_CONGE This venom insulin, from a fish-hunting cone snail, facilitates prey capture by rapidly inducing hypoglycemic shock (PubMed:25605914, PubMed:27617429). It is one of the smallest known insulin found in nature and lacks the C-terminal segment of the B chain that, in human insulin, mediates engagement of the insulin receptor (INSR) and assembly of the hormone's hexameric storage form (PubMed:27617429). Despite lacking this segment, it both binds and activates human insulin receptor (long isoform (HIR-B)) with a high potency (EC(50)=16.28 nM) (PubMed:30747102, PubMed:27617429). In vivo, intraperitoneal injection of this peptide into zebrafish lowers blood glucose with the same potency than human insulin (PubMed:25605914, PubMed:30747102). In addition, when applied to water, this peptide reduces overall locomotor activity of zebrafish larvae, observed as a significant decrease in the percentage of time spent swimming and movement frequency (PubMed:25605914). When tested on a mouse model of diabetes, this insulin also lowers blood glucose with a 10-fold lower potency than human insulin (PubMed:30747102).[1] [2] [3] Publication Abstract from PubMedInsulins 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, 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 of receptor affinity. Here, we 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. Our crystal structure of Con-Ins G1 reveals a tertiary structure highly similar to that of human insulin and indicates how Con-Ins G1's lack of an equivalent to the key receptor-engaging residue PheB24 is mitigated. These findings may facilitate efforts to design ultrarapid-acting therapeutic insulins. A minimized human insulin-receptor-binding motif revealed in a Conus geographus venom insulin.,Menting JG, Gajewiak J, MacRaild CA, Chou DH, Disotuar MM, Smith NA, Miller C, Erchegyi J, Rivier JE, Olivera BM, Forbes BE, Smith BJ, Norton RS, Safavi-Hemami H, Lawrence MC Nat Struct Mol Biol. 2016 Sep 12. doi: 10.1038/nsmb.3292. PMID:27617429[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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