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

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    Author
    Xiong, X; Menting, JG; Disotuar, MM; Smith, NA; Delaine, CA; Ghabash, G; Agrawal, R; Wang, X; He, X; Fisher, SJ; ...
    Date
    2020-06-01
    Source Title
    Nature Structural and Molecular Biology
    Publisher
    NATURE PUBLISHING GROUP
    University of Melbourne Author/s
    Lawrence, Michael
    Affiliation
    Medical Biology (W.E.H.I.)
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    Xiong, X., Menting, J. G., Disotuar, M. M., Smith, N. A., Delaine, C. A., Ghabash, G., Agrawal, R., Wang, X., He, X., Fisher, S. J., MacRaild, C. A., Norton, R. S., Gajewiak, J., Forbes, B. E., Smith, B. J., Safavi-Hemami, H., Olivera, B., Lawrence, M. C. & Chou, D. H. -C. (2020). A structurally minimized yet fully active insulin based on cone-snail venom insulin principles. NATURE STRUCTURAL & MOLECULAR BIOLOGY, 27 (7), pp.615-+. https://doi.org/10.1038/s41594-020-0430-8.
    Access Status
    Access this item via the Open Access location
    URI
    http://hdl.handle.net/11343/254484
    DOI
    10.1038/s41594-020-0430-8
    Open Access URL
    https://europepmc.org/articles/PMC7374640?pdf=render
    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.

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