Allosteric Regulation and Inhibition of Coronavirus 3CLpro Revealed by HDX-MS
文献类型：期刊论文
| 作者 | Song, Ning3,4; Zheng, Wen2; Song, Bin1; Zheng, Jie3,4 |
| 刊名 | CHEMBIOCHEM
 |
| 出版日期 | 2024-07-02 |
| 卷号 | 25期号:13页码:9 |
| 关键词 | coronavirus 3Clpro allosteric inhibitor |
| ISSN号 | 1439-4227 |
| DOI | 10.1002/cbic.202400001 |
| 通讯作者 | Zheng, Jie(jzheng@simm.ac.cn) |
| 英文摘要 | Coronavirus (CoV) infections have caused contagious and fatal respiratory diseases in humans worldwide. CoV 3-chymotrypsin-like proteases (3CLpro or Mpro) play an important role in viral maturation, and maintenance of their dimeric conformation is crucial for viral activity. Therefore, allosterically regulated dimerization of 3CLpro can be employed as a drug development target. Here, we investigated the allosteric regulatory mechanism of 3CLpro dimerization by using hydrogen/deuterium exchange coupled with mass spectrometry (HDX-MS) technology. We found that the FLAG tag directly coupled to the N-finger of 3CLpro significantly increased HDX kinetics at the dimer interface, and 3CLpro transformed from a dimer to a monomer. The 3CLpro mutants of SARS-CoV-2, which are monomeric, also exhibited increased deuterium exchange. Binding of the allosteric inhibitor Gastrodenol to most betacoronavirus 3CLpros led to increased allosteric deuterium exchange, resulting in the monomeric conformation of the CoV 3CLpro upon binding. Molecular dynamics (MD) simulation analysis further indicated the molecular mechanism of action of Gastrodenol on CoV 3CLpro: binding of Gastrodenol to SARS-CoV-2 3CLpro destroyed the hydrogen bond in the dimer interface. These results suggest that Gastrodenol may be a potential broad-spectrum anti-betacoronavirus drug. The viruses invade the host and produce mature 3CLpro dimers, which are depolymerized into inactive monomeric forms by the allosteric inhibitor Gastrodenol. image |
| WOS关键词 | MECHANISMS ; DISCOVERY ; PROTEASES ; BISMUTH ; COMPLEX ; SARS |
| 资助项目 | National Natural Science Foundation of China ; Science and Technology Commission of Shanghai Municipality[23JC1403400] ; [32222048] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001251312700001 |
| 出版者 | WILEY-V C H VERLAG GMBH |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/311917]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Zheng, Jie |
| 作者单位 | 1.Shanghai Jiao Tong Univ, Shanghai Inst Virol, Sch Med, 227 South Chongqing Rd, Shanghai 200025, Peoples R China 2.Hubei Yuanda Biotechnol Co Ltd, CADD Comp Aided Prot Design Simulator, Bldg B6, Wuhan 430000, Hubei, Peoples R China 3.Univ Chinese Acad Sci, 1 Yanqihu East Rd, Beijing 101408, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med, Immunol Dis Res Ctr, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Song, Ning,Zheng, Wen,Song, Bin,et al. Allosteric Regulation and Inhibition of Coronavirus 3CLpro Revealed by HDX-MS[J]. CHEMBIOCHEM,2024,25(13):9. |
| APA | Song, Ning,Zheng, Wen,Song, Bin,&Zheng, Jie.(2024).Allosteric Regulation and Inhibition of Coronavirus 3CLpro Revealed by HDX-MS.CHEMBIOCHEM,25(13),9. |
| MLA | Song, Ning,et al."Allosteric Regulation and Inhibition of Coronavirus 3CLpro Revealed by HDX-MS".CHEMBIOCHEM 25.13(2024):9. |
入库方式： OAI收割
来源：上海药物研究所
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