Symmetric and asymmetric receptor conformation continuum induced by a new insulin

Xiaochun Xiong, Alan Blakely, Jin Hwan Kim, John G. Menting, Ingmar B. Schäfer, Heidi L. Schubert, Rahul Agrawal, Theresia Gutmann, Carlie Delaine, Yi Wolf Zhang, Gizem Olay Artik, Allanah Merriman, Debbie Eckert, Michael C. Lawrence, Ünal Coskun, Simon J. Fisher, Briony E. Forbes, Helena Safavi-Hemami, Christopher P. Hill, Danny Hung-Chieh Chou

Research output: Contribution to journalArticlepeer-review

Abstract

Cone snail venoms contain a wide variety of bioactive peptides, including insulin-like molecules with distinct structural features, binding modes and biochemical properties. Here, we report an active humanized cone snail venom insulin with an elongated A chain and a truncated B chain, and use cryo-electron microscopy (cryo-EM) and protein engineering to elucidate its interactions with the human insulin receptor (IR) ectodomain. We reveal how an extended A chain can compensate for deletion of B-chain residues, which are essential for activity of human insulin but also compromise therapeutic utility by delaying dissolution from the site of subcutaneous injection. This finding suggests approaches to developing improved therapeutic insulins. Curiously, the receptor displays a continuum of conformations from the symmetric state to a highly asymmetric low-abundance structure that displays coordination of a single humanized venom insulin using elements from both of the previously characterized site 1 and site 2 interactions.

Original languageEnglish
Pages (from-to)511-519
Number of pages9
JournalNature Chemical Biology
Volume18
Issue number5
Early online date14 Mar 2022
DOIs
Publication statusPublished - May 2022

Keywords

  • insulin
  • Cone snail venoms
  • bioactive peptides
  • molecules
  • biochemical
  • insulin receptor
  • IR
  • ectodomain
  • therapeutic

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