Fish-hunting cone snail venoms are a rich source of minimized ligands of the vertebrate insulin receptor

Elife. 2019 Feb 12;8:e41574. doi: 10.7554/eLife.41574.

Abstract

The fish-hunting marine cone snail Conus geographus uses a specialized venom insulin to induce hypoglycemic shock in its prey. We recently showed that this venom insulin, Con-Ins G1, has unique characteristics relevant to the design of new insulin therapeutics. Here, we show that fish-hunting cone snails provide a rich source of minimized ligands of the vertebrate insulin receptor. Insulins from C. geographus, Conus tulipa and Conus kinoshitai exhibit diverse sequences, yet all bind to and activate the human insulin receptor. Molecular dynamics reveal unique modes of action that are distinct from any other insulins known in nature. When tested in zebrafish and mice, venom insulins significantly lower blood glucose in the streptozotocin-induced model of diabetes. Our findings suggest that cone snails have evolved diverse strategies to activate the vertebrate insulin receptor and provide unique insight into the design of novel drugs for the treatment of diabetes.

Keywords: biochemistry; chemical biology; cone snail; diabetes; hypoglycemic shock; insulin; prey capture; venom.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / chemistry
  • Conus Snail / chemistry*
  • Disease Models, Animal
  • Humans
  • Hypoglycemia / pathology
  • Insulin / chemistry
  • Insulin / genetics
  • Insulin / metabolism*
  • Mice
  • Molecular Dynamics Simulation
  • Mollusk Venoms / metabolism*
  • Poisoning / pathology
  • Poisons / metabolism*
  • Receptor, Insulin / agonists*
  • Receptor, Insulin / chemistry
  • Zebrafish

Substances

  • Antigens, CD
  • Insulin
  • Mollusk Venoms
  • Poisons
  • INSR protein, human
  • Receptor, Insulin