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- W3110820488 abstract "Fibroblast growth factor 21 (FGF21) is a regulator of glucose and lipid metabolism. It has been widely considered as a promising candidate for the treatment of type 2 diabetes mellitus (T2DM) and other related metabolic disorders. However, lack of structural and dynamic information has limited FGF21-based drug development. Here, using nuclear magnetic resonance (NMR) spectroscopy, we determine the structure of FGF21 and find that its non-canonical flexible β-trefoil conformation affects the folding of β2-β3 hairpin and further overall protein stability. To modulate folding dynamics, we designed an FGF21-FGF19 chimera, FGF21SS . As expected, FGF21SS shows better thermostability without inducing hepatocyte proliferation. Functional characterization of FGF21SS shows its better insulin sensitivity, reduced inflammation in 3T3-L1 adipocytes, and lower blood glucose and insulin levels in ob/ob mice compared with wild type. Our dynamics-based rational design provides a promising approach for FGF21-based therapeutic development against T2DM." @default.
- W3110820488 created "2020-12-21" @default.
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- W3110820488 date "2020-12-09" @default.
- W3110820488 modified "2023-10-14" @default.
- W3110820488 title "Dynamic folding modulation generates FGF21 variant against diabetes" @default.
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- W3110820488 doi "https://doi.org/10.15252/embr.202051352" @default.
- W3110820488 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/7788455" @default.
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