2026-10-14T15:21:34Z https://www.scidb.cn/oai

10.57760/sciencedb.03004 2022-11-24T14:53:36Z

2022-11-24 Dynamic folding modulation generates FGF21 variant against diabetes doi:10.57760/sciencedb.03004 en 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 b-trefoil conformation affects the folding of b2-b3 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 inob/ob mice compared with wild type. Our dynamics-based rational design provides a promising approach for FGF21-based therapeutic development against T2DM. anti-diabetes; disulfide bond mutation; FGF21; folding dynamics; NMR Lei Zhu PUBLIC https://creativecommons.org/licenses/by-nc-sa/4.0/ dataset http://www.doi.org/10.15252/embr.202051352 Science Data Bank