A structurally minimized yet fully active insulin based on cone-snail venom insulin principles
- Xiong, X; Menting, JG; Disotuar, MM; Smith, NA; Delaine, CA; Ghabash, G; Agrawal, R; Wang, X; He, X; Fisher, SJ; MacRaild, CA; Norton, RS; Gajewiak, J; Forbes, BE; Smith, BJ; Safavi-Hemami, H; Olivera, B; Lawrence, MC; Chou, DH;
- Journal Title
- Nature Structural & Molecular Biology
- Publication Type
- Journal epub ahead of print
- 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.
- WEHI Research Division(s)
- Structural Biology
- PubMed ID
- Publisher's Version
- Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2020-07-02 01:44:21Last Modified: 2020-07-02 02:39:11