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Distal mutation V486M disrupts the catalytic activity of DPP4 by affecting the flap of the propeller domain

文献类型：期刊论文

作者Li, Teng-teng1,2; Peng, Cheng3,4,5; Wang, Ji-qiu6; Xu, Zhi-jian3,4,5; Su, Ming-bo1; Li, Jia1,2; Zhu, Wei-liang3,4,5; Li, Jing-ya1
刊名ACTA PHARMACOLOGICA SINICA
出版日期2021-12-14
页码9
关键词DPP4 distal mutation enzymatic activity molecular dynamics simulation structure-function mechanism
ISSN号1671-4083
DOI10.1038/s41401-021-00818-x
通讯作者Zhu, Wei-liang(wlzhu@simm.ac.cn) ; Li, Jing-ya(jyli@simm.ac.cn)
英文摘要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.
WOS关键词MOLECULAR-DYNAMICS SIMULATIONS ; DIPEPTIDYL PEPTIDASE-IV ; INSULIN-RESISTANCE ; CRYSTAL-STRUCTURE ; INHIBITION ; INFLAMMATION ; REVEALS ; SITE ; CD26
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] ; National Key R&D Program of China[2017YFB0202601]
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000730083700003
出版者NATURE PUBL GROUP
源URL[http://119.78.100.183/handle/2S10ELR8/299238]  
专题新药研究国家重点实验室
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
推荐引用方式
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,2021:9.
APA Li, Teng-teng.,Peng, Cheng.,Wang, Ji-qiu.,Xu, Zhi-jian.,Su, Ming-bo.,...&Li, Jing-ya.(2021).Distal mutation V486M disrupts the catalytic activity of DPP4 by affecting the flap of the propeller domain.ACTA PHARMACOLOGICA SINICA,9.
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 (2021):9.

入库方式： OAI收割

来源：上海药物研究所

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