A minimized human insulin-receptor-binding motif revealed in a Conus geographus venom insulin
Journal Title
Nat Struct Mol Biol
Publication Type
Journal Article
Abstract
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, 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.
Publisher
NPG
WEHI Research Division(s)
Structural Biology
PubMed ID
27617429
Publisher's Version
https://doi.org/10.1038/nsmb.3292
NHMRC Grants
NHMRC/1058233
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2016-10-03 03:38:08
Last Modified: 2018-03-09 12:25:38
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