Dynamic folding modulation generates FGF21 variant against diabetes
文献类型：期刊论文
| 作者 | Zhu, Lei2 ; Zhao, Hongxin2; Liu, Juanjuan2; Cai, Hao1; Wu, Bo2; Liu, Zhijun2; Zhou, Shu2; Liu, Qingsong2; Li, Xiaokun5; Bao, Bin1
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| 刊名 | EMBO REPORTS
 |
| 出版日期 | 2021-01-07 |
| 卷号 | 22 |
| ISSN号 | 1469-221X |
| 关键词 | anti‐ diabetes disulfide bond mutation FGF21 folding dynamics NMR |
| 通讯作者 | Dai, Han(daihan@hmfl.ac.cn) ; Wang, Junfeng(junfeng@hmfl.ac.cn) |
| 英文摘要 | 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 beta-trefoil conformation affects the folding of beta 2-beta 3 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. |
| 资助项目 | National Natural Science Foundation of China[U1532269] ; National Natural Science Foundation of China[31800645] ; National Natural Science Foundation of China[21673244] ; National Natural Science Foundation of China[31100539] ; High Magnetic Field Laboratory of Anhui Province ; Ministry of Science and Technology of China[2016YFA0400900] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Cell Biology |
| 语种 | 英语 |
| 出版者 | WILEY |
| WOS记录号 | WOS:000596607300001 |
| 资助机构 | National Natural Science Foundation of China ; High Magnetic Field Laboratory of Anhui Province ; Ministry of Science and Technology of China |
| 源URL | [http://ir.hfcas.ac.cn:8080/handle/334002/123230]  |
| 专题 | 中国科学院合肥物质科学研究院 |
| 通讯作者 | Dai, Han; Wang, Junfeng |
| 作者单位 | 1.Hefei Univ Technol, Sch Biotechnol & Food Engn, Hefei, Peoples R China 2.Chinese Acad Sci, Hefei Inst Phys Sci, CAS Key Lab High Magnet Field & Ion Beam Phys Bio, High Magnet Field Lab, Hefei, Peoples R China 3.Anhui Univ, Inst Phys Sci & Informat Technol, Hefei, Peoples R China 4.Univ Sci & Technol China, Hefei, Peoples R China 5.Wenzhou Med Univ, Sch Pharmaceut Sci, Chem Biol Res Ctr, Wenzhou, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhu, Lei,Zhao, Hongxin,Liu, Juanjuan,et al. Dynamic folding modulation generates FGF21 variant against diabetes[J]. EMBO REPORTS,2021,22. |
| APA | Zhu, Lei.,Zhao, Hongxin.,Liu, Juanjuan.,Cai, Hao.,Wu, Bo.,...&Wang, Junfeng.(2021).Dynamic folding modulation generates FGF21 variant against diabetes.EMBO REPORTS,22. |
| MLA | Zhu, Lei,et al."Dynamic folding modulation generates FGF21 variant against diabetes".EMBO REPORTS 22(2021). |
入库方式： OAI收割
来源：合肥物质科学研究院
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