期刊
NATURE STRUCTURAL & MOLECULAR BIOLOGY
卷 27, 期 7, 页码 615-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41594-020-0430-8
关键词
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资金
- Australian Research Training Scholarship
- Australian National Health and Medical Research Council
- Australian Government [LE170100200]
- CSIRO Protein Production Facility [cIR485, IR310]
- NIDDK [DK120430, GM125001]
- Juvenile Diabetes Research Foundation [5-CDA-2018-572-A-N, 1-INO-2017-441-A-N]
- Australian National Health and Medical Research Council (NHMRC) [APP1143546, APP1099595]
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. Insights from structural biology lead to the development of mini-Ins-a human des-octapeptide insulin analog that is monomeric and has receptor binding affinity and in vitro and in vivo activities comparable to those of human insulin.
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