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    Insulin in motion: The A6-A11 disulfide bond allosterically modulates structural transitions required for insulin activity

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    Author
    van Lierop, B; Ong, SC; Belgi, A; Delaine, C; Andrikopoulos, S; Haworth, NL; Menting, JG; Lawrence, MC; Robinson, AJ; Forbes, BE
    Date
    2017-12-08
    Source Title
    Scientific Reports
    Publisher
    NATURE PUBLISHING GROUP
    University of Melbourne Author/s
    Andrikopoulos, Sofianos; Lawrence, Michael
    Affiliation
    Medical Biology (W.E.H.I.)
    Medicine and Radiology
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    van Lierop, B., Ong, S. C., Belgi, A., Delaine, C., Andrikopoulos, S., Haworth, N. L., Menting, J. G., Lawrence, M. C., Robinson, A. J. & Forbes, B. E. (2017). Insulin in motion: The A6-A11 disulfide bond allosterically modulates structural transitions required for insulin activity. SCIENTIFIC REPORTS, 7 (1), https://doi.org/10.1038/s41598-017-16876-3.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/257642
    DOI
    10.1038/s41598-017-16876-3
    Abstract
    The structural transitions required for insulin to activate its receptor and initiate regulation of glucose homeostasis are only partly understood. Here, using ring-closing metathesis, we substitute the A6-A11 disulfide bond of insulin with a rigid, non-reducible dicarba linkage, yielding two distinct stereo-isomers (cis and trans). Remarkably, only the cis isomer displays full insulin potency, rapidly lowering blood glucose in mice (even under insulin-resistant conditions). It also posseses reduced mitogenic activity in vitro. Further biophysical, crystallographic and molecular-dynamics analyses reveal that the A6-A11 bond configuration directly affects the conformational flexibility of insulin A-chain N-terminal helix, dictating insulin's ability to engage its receptor. We reveal that in native insulin, contraction of the Cα-Cα distance of the flexible A6-A11 cystine allows the A-chain N-terminal helix to unwind to a conformation that allows receptor engagement. This motion is also permitted in the cis isomer, with its shorter Cα-Cα distance, but prevented in the extended trans analogue. These findings thus illuminate for the first time the allosteric role of the A6-A11 bond in mediating the transition of the hormone to an active conformation, significantly advancing our understanding of insulin action and opening up new avenues for the design of improved therapeutic analogues.

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