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

23 Scopus citations

Abstract

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
Volume27
Issue number7
DOIs
StatePublished - Jul 1 2020

Bibliographical note

Funding Information:
X.X. is a Juvenile Diabetes Research Foundation Postdoctoral Fellow. N.A.S. acknowledges receipt of an Australian Research Training Scholarship. R.S.N acknowledges fellowship support from the Australian National Health and Medical Research Council. Part of this work was undertaken using resources from the National Computational Infrastructure, which is supported by the Australian Government and provided through Intersect Australia Ltd, and through the HPC-GPGPU Facility, which was established with the assistance of a Linkage Infrastructure, Equipment and Facilities grant (LE170100200). We thank the CSIRO Protein Production Facility for the production under contract of cIR485, the precursor of IR310.T. Crystallization screening was undertaken at the CSIRO Collaborative Crystallisation Centre (www.csiro.au/C3), Melbourne, Australia. This research was undertaken in part using the MX2 beamline at the Australian Synchrotron, part of the Australian Nuclear Science and Technology Organisation, and made use of the ACRF detector. We thank M. Margetts for production of the heavy and light chain fragments of Fv83-7. This work is supported by NIDDK (DK120430, GM125001 to D.H.C.), the Juvenile Diabetes Research Foundation (5-CDA-2018-572-A-N to D.H.C. and 1-INO-2017-441-A-N to H.S.H.), the Australian National Health and Medical Research Council (NHMRC) Project grant nos. APP1143546 (to M.C.L., R.S.N., B.J.S., B.E.F. and D.H.C.) and APP1099595 (to M.C.L.). M.C.L.’s research is also made possible at The Walter and Eliza Hall Institute of Medical Research through Victorian State Government Operational Infrastructure Support and the Australian NHMRC Independent Research Institutes Infrastructure Support Scheme.

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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