A minimized human insulin-receptor-binding motif revealed in a Conus geographus venom insulin Academic Article uri icon

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.

authors

  • Menting, JG
  • Gajewiak, J
  • MacRaild, CA
  • Chou, DH-C
  • Disotuar, MM
  • Smith, NA
  • Miller, C
  • Erchegyi, J
  • Rivier, JE
  • Olivera, BM
  • Forbes, BE
  • Smith, BJ
  • Norton, RS
  • Safavi-Hemami, H
  • Lawrence, MC

publication date

  • 2016