High Magnetic Field Laboratory, CAS Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, China.
School of Biotechnology & Food Engineering, Hefei University of Technology, Hefei, China.
EMBO Rep. 2021 Jan 7;22(1):e51352. doi: 10.15252/embr.202051352. Epub 2020 Dec 9.
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, FGF21 . As expected, FGF21 shows better thermostability without inducing hepatocyte proliferation. Functional characterization of FGF21 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.
成纤维细胞生长因子 21（FGF21）是调节葡萄糖和脂质代谢的物质。它被广泛认为是治疗 2 型糖尿病（T2DM）和其他相关代谢紊乱的有前途的候选药物。然而，缺乏结构和动态信息限制了基于 FGF21 的药物开发。在这里，我们使用核磁共振（NMR）光谱法确定了 FGF21 的结构，发现其非典型的灵活 β-三叶折叠构象影响β2-β3 发夹的折叠，进而影响整体蛋白质稳定性。为了调节折叠动力学，我们设计了 FGF21-FGF19 嵌合体，即 FGF21。正如预期的那样，FGF21 表现出更好的热稳定性，而不会诱导肝细胞增殖。FGF21 的功能特征表明，与野生型相比，其胰岛素敏感性更好，3T3-L1 脂肪细胞中的炎症减少，ob/ob 小鼠的血糖和胰岛素水平降低。我们基于动力学的合理设计为基于 FGF21 的 T2DM 治疗开发提供了一种有前途的方法。
