Dynamic folding modulation generates FGF21 variant against diabetes

	Dynamic folding modulation generates FGF21 variant against diabetes
	Zhu, Lei 4; Zhao, Hongxin 4; Liu, Juanjuan 4; Cai, Hao 1; Wu, Bo 4; Liu, Zhijun 4; Zhou, Shu 4; Liu, Qingsong 4; Li, Xiaokun 2; Bao, Bin 1
刊名	EMBO REPORTS
	2021-01-07
卷号	22
关键词	anti‐ diabetes disulfide bond mutation FGF21 folding dynamics NMR
ISSN号	1469-221X
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
内容类型	期刊论文
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.Wenzhou Med Univ, Sch Pharmaceut Sci, Chem Biol Res Ctr, Wenzhou, Peoples R China 3.Univ Sci & Technol China, Hefei, Peoples R China 4.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 5.Anhui Univ, Inst Phys Sci & Informat Technol, Hefei, 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).