A structurally minimized yet fully active insulin based on cone-snail venom insulin principles

Xiaochun Xiong, John G. Menting, Maria M. Disotuar, Nicholas A. Smith, Carlie A. Delaine, Gabrielle Ghabash, Rahul Agrawal, Xiaomin Wang, Xiao He, Simon J. Fisher, Christopher A. MacRaild, Raymond S. Norton, Joanna Gajewiak, Briony E. Forbes, Brian J. Smith, Helena Safavi-Hemami, Baldomero Olivera, Michael C. Lawrence, Danny Hung Chieh Chou

Research output: Contribution to journalArticlepeer-review

33 Scopus citations


Human insulin and its current therapeutic analogs all show propensity, albeit varyingly, to self-associate into dimers and hexamers, which delays their onset of action and makes blood glucose management difficult for people with diabetes. Recently, we described a monomeric, insulin-like peptide in cone-snail venom with moderate human insulin-like bioactivity. Here, with insights from structural biology studies, we report the development of mini-Ins—a human des-octapeptide insulin analog—as a structurally minimal, full-potency insulin. Mini-Ins is monomeric and, despite the lack of the canonical B-chain C-terminal octapeptide, has similar receptor binding affinity to human insulin. Four mutations compensate for the lack of contacts normally made by the octapeptide. Mini-Ins also has similar in vitro insulin signaling and in vivo bioactivities to human insulin. The full bioactivity of mini-Ins demonstrates the dispensability of the PheB24–PheB25–TyrB26 aromatic triplet and opens a new direction for therapeutic insulin development.

Original languageEnglish
Pages (from-to)615-624
Number of pages10
JournalNature Structural and Molecular Biology
Issue number7
StatePublished - Jul 1 2020

Bibliographical note

Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology


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