A structurally minimized yet fully active insulin based on cone-snail venom insulin principles
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A structurally minimized yet fully active insulin based on cone-snail venom insulin principles. / Xiong, Xiaochun; Menting, John G.; Disotuar, Maria M.; Smith, Nicholas A.; Delaine, Carlie A.; Ghabash, Gabrielle; Agrawal, Rahul; Wang, Xiaomin; He, Xiao; Fisher, Simon J.; MacRaild, Christopher A.; Norton, Raymond S.; Gajewiak, Joanna; Forbes, Briony E.; Smith, Brian J.; Safavi-Hemami, Helena; Olivera, Baldomero; Lawrence, Michael C.; Chou, Danny Hung Chieh.
I: Nature Structural and Molecular Biology, Bind 27, 2020, s. 615-624.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - A structurally minimized yet fully active insulin based on cone-snail venom insulin principles
AU - Xiong, Xiaochun
AU - Menting, John G.
AU - Disotuar, Maria M.
AU - Smith, Nicholas A.
AU - Delaine, Carlie A.
AU - Ghabash, Gabrielle
AU - Agrawal, Rahul
AU - Wang, Xiaomin
AU - He, Xiao
AU - Fisher, Simon J.
AU - MacRaild, Christopher A.
AU - Norton, Raymond S.
AU - Gajewiak, Joanna
AU - Forbes, Briony E.
AU - Smith, Brian J.
AU - Safavi-Hemami, Helena
AU - Olivera, Baldomero
AU - Lawrence, Michael C.
AU - Chou, Danny Hung Chieh
N1 - Author Correction: https://www.nature.com/articles/s41594-020-0460-2
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
U2 - 10.1038/s41594-020-0430-8
DO - 10.1038/s41594-020-0430-8
M3 - Journal article
C2 - 32483339
AN - SCOPUS:85085878153
VL - 27
SP - 615
EP - 624
JO - Nature Structural and Molecular Biology
JF - Nature Structural and Molecular Biology
SN - 1545-9993
ER -
ID: 244531737