A minimized human insulin-receptor-binding motif revealed in a Conus geographus venom insulin

John G. Menting, Joanna Gajewiak, Christopher MacRaild, Danny Hung Chieh Chou, Maria M. Disotuar, Nicholas A Smith, Charleen Miller, Judit Erchegyi, Jean E. Rivier, Baldomero M. Olivera, Briony E. Forbes, Brian J Smith, Raymond Norton, Helena Safavi-Hemami, Michael C. Lawrence

Research output: Contribution to journalArticleResearchpeer-review

40 Citations (Scopus)

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 Phe B24 is mitigated. These findings may facilitate efforts to design ultrarapid-acting therapeutic insulins.

Original languageEnglish
Pages (from-to)916-920
Number of pages5
JournalNature Structural & Molecular Biology
Volume23
Issue number10
DOIs
Publication statusPublished - 1 Oct 2016

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