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Distal mutation V486M disrupts the catalytic activity of DPP4 by affecting the flap of the propeller domain
2022-08
发表期刊ACTA PHARMACOLOGICA SINICA (IF:6.9[JCR-2023],7.6[5-Year])
ISSN1671-4083
EISSN1745-7254
发表状态已发表
DOI10.1038/s41401-021-00818-x
摘要Dipeptidyl peptidase-4 (DPP4) plays a crucial role in regulating the bioactivity of glucagon-like peptide-1 (GLP-1) that enhances insulin secretion and pancreatic beta-cell proliferation, making it a therapeutic target for type 2 diabetes. Although the crystal structure of DPP4 has been determined, its structure-function mechanism is largely unknown. Here, we examined the biochemical properties of sporadic human DPP4 mutations distal from its catalytic site, among which V486M ablates DPP4 dimerization and causes loss of enzymatic activity. Unbiased molecular dynamics simulations revealed that the distal V486M mutation induces a local conformational collapse in a beta-propeller loop (residues 234-260, defined as the flap) and disrupts the dimerization of DPP4. The "open/closed" conformational transitions of the flap whereby capping the active site, are involved in the enzymatic activity of DPP4. Further site-directed mutagenesis guided by theoretical predictions verified the importance of the conformational dynamics of the flap for the enzymatic activity of DPP4. Therefore, the current studies that combined theoretical modeling and experimental identification, provide important insights into the biological function of DPP4 and allow for the evaluation of directed DPP4 genetic mutations before initiating clinical applications and drug development.
关键词DPP4 distal mutation enzymatic activity molecular dynamics simulation structure-function mechanism
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收录类别SCI ; SCIE
语种英语
资助项目National Natural Science Foundation of China[92057116] ; National Science and Technology Major Project[2018ZX09711002-018] ; Strategic Priority Research Program of Chinese Academy of Sciences[XDA12040204] ; Shanghai Commission of Science and Technology[18431900900] ; National Key R&D Program of China["2016YFA0502301","2017YFB0202601"]
WOS研究方向Chemistry ; Pharmacology & Pharmacy
WOS类目Chemistry, Multidisciplinary ; Pharmacology & Pharmacy
WOS记录号WOS:000730083700003
出版者NATURE PUBL GROUP
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文献类型期刊论文
条目标识符https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/138706
专题生命科学与技术学院_硕士生
生命科学与技术学院_特聘教授组_李佳组
通讯作者Zhu, Wei-liang; Li, Jing-ya
作者单位
1.Chinese Acad Sci, Natl Drug Screening Ctr, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
2.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
4.Chinese Acad Sci, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
5.Univ Chinese Acad Sci, Sch Pharm, Beijing 100049, Peoples R China
6.Shanghai Jiao Tong Univ Sch Med SJTUSM, Ruijin Hosp, China Natl Res Ctr Metab Dis, Dept Endocrinol & Metab,Natl Key Lab Med Genomes, Shanghai 200025, Peoples R China
第一作者单位生命科学与技术学院
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GB/T 7714
Li, Teng-teng,Peng, Cheng,Wang, Ji-qiu,et al. Distal mutation V486M disrupts the catalytic activity of DPP4 by affecting the flap of the propeller domain[J]. ACTA PHARMACOLOGICA SINICA,2022.
APA Li, Teng-teng.,Peng, Cheng.,Wang, Ji-qiu.,Xu, Zhi-jian.,Su, Ming-bo.,...&Li, Jing-ya.(2022).Distal mutation V486M disrupts the catalytic activity of DPP4 by affecting the flap of the propeller domain.ACTA PHARMACOLOGICA SINICA.
MLA Li, Teng-teng,et al."Distal mutation V486M disrupts the catalytic activity of DPP4 by affecting the flap of the propeller domain".ACTA PHARMACOLOGICA SINICA (2022).
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