PMID- 33295692
OWN - NLM
STAT- MEDLINE
DCOM- 20210531
LR  - 20240330
IS  - 1469-3178 (Electronic)
IS  - 1469-221X (Print)
IS  - 1469-221X (Linking)
VI  - 22
IP  - 1
DP  - 2021 Jan 7
TI  - Dynamic folding modulation generates FGF21 variant against diabetes.
PG  - e51352
LID - 10.15252/embr.202051352 [doi]
LID - e51352
AB  - 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 beta2-beta3 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.
CI  - (c) 2020 The Authors.
FAU - Zhu, Lei
AU  - Zhu L
AUID- ORCID: 0000-0001-5003-9059
AD  - 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.
FAU - Zhao, Hongxin
AU  - Zhao H
AD  - 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.
FAU - Liu, Juanjuan
AU  - Liu J
AD  - 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.
FAU - Cai, Hao
AU  - Cai H
AD  - School of Biotechnology & Food Engineering, Hefei University of Technology, 
      Hefei, China.
FAU - Wu, Bo
AU  - Wu B
AD  - 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.
FAU - Liu, Zhijun
AU  - Liu Z
AD  - 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.
FAU - Zhou, Shu
AU  - Zhou S
AD  - 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.
FAU - Liu, Qingsong
AU  - Liu Q
AD  - 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.
FAU - Li, Xiaokun
AU  - Li X
AD  - Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou 
      Medical University, Wenzhou, China.
FAU - Bao, Bin
AU  - Bao B
AD  - Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou 
      Medical University, Wenzhou, China.
FAU - Liu, Jian
AU  - Liu J
AUID- ORCID: 0000-0002-3220-1240
AD  - University of Science and Technology of China, Hefei, China.
FAU - Dai, Han
AU  - Dai H
AUID- ORCID: 0000-0001-9234-8386
AD  - 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.
FAU - Wang, Junfeng
AU  - Wang J
AUID- ORCID: 0000-0002-9608-6851
AD  - 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.
AD  - Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou 
      Medical University, Wenzhou, China.
AD  - Institute of Physical Science and Information Technology, Anhui University, 
      Hefei, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20201209
PL  - England
TA  - EMBO Rep
JT  - EMBO reports
JID - 100963049
RN  - 0 (Blood Glucose)
RN  - 0 (fibroblast growth factor 21)
RN  - 62031-54-3 (Fibroblast Growth Factors)
SB  - IM
MH  - Animals
MH  - Blood Glucose
MH  - *Diabetes Mellitus, Type 2/drug therapy/genetics
MH  - *Fibroblast Growth Factors/genetics
MH  - *Insulin Resistance/genetics
MH  - Mice
PMC - PMC7788455
OTO - NOTNLM
OT  - FGF21
OT  - NMR
OT  - anti-diabetes
OT  - disulfide bond mutation
OT  - folding dynamics
COIS- The authors declare that they have no conflict of interest.
EDAT- 2020/12/10 06:00
MHDA- 2021/06/01 06:00
PMCR- 2022/01/07
CRDT- 2020/12/09 08:40
PHST- 2020/07/18 00:00 [received]
PHST- 2020/10/10 00:00 [revised]
PHST- 2020/10/15 00:00 [accepted]
PHST- 2020/12/10 06:00 [pubmed]
PHST- 2021/06/01 06:00 [medline]
PHST- 2020/12/09 08:40 [entrez]
PHST- 2022/01/07 00:00 [pmc-release]
AID - EMBR202051352 [pii]
AID - 10.15252/embr.202051352 [doi]
PST - ppublish
SO  - EMBO Rep. 2021 Jan 7;22(1):e51352. doi: 10.15252/embr.202051352. Epub 2020 Dec 9.