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^SS. As expected, FGF21^SS shows better thermostability without inducing hepatocyte proliferation. Functional characterization of FGF21^SS 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.

中文翻译：

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动态折叠调制产生抗糖尿病的 FGF21 变体

成纤维细胞生长因子 21 (FGF21) 是葡萄糖和脂质代谢的调节剂。它已被广泛认为是治疗 2 型糖尿病 (T2DM) 和其他相关代谢疾病的有希望的候选药物。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) 光谱确定了 FGF21 的结构，并发现其非典型的柔性 β-三叶草构象会影响 β2-β3 发夹的折叠和进一步的整体蛋白质稳定性。为了调节折叠动力学，我们设计了 FGF21-FGF19 嵌合体 FGF21 ^SS。正如预期的那样，FGF21 ^SS在不诱导肝细胞增殖的情况下表现出更好的热稳定性。^{FGF21 SS}的功能表征与野生型相比， ob/ob小鼠的胰岛素敏感性更好，3T3-L1 脂肪细胞炎症减少，血糖和胰岛素水平更低。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景的方法。