Substrate recognition and cleavage mechanism of the monkeypox virus core protease
文献类型：期刊论文
| 作者 | Gao, Yan16,17,18; Xie, Xiong14,15; Zhang, Xiaoyu13,17,18; Cao, Junyuan11,12; Lan, Weiqi17,18; You, Tian17,18; Li, Dongxu17,18; Dong, Xuxue10,17,18; Dai, Wenhao9,14,15; Xiang, Yingchun11 |
| 刊名 | NATURE
 |
| 出版日期 | 2025-04-22 |
| 页码 | 29 |
| ISSN号 | 0028-0836 |
| DOI | 10.1038/s41586-025-09014-x |
| 英文摘要 | Poxviruses cause severe diseases, including smallpox and mpox, that pose major threats to human health. The poxvirus core protease (CorePro) is essential for viral maturation and is highly conserved in poxviruses, making it an attractive antiviral target1. However, the structure of CorePro remains unknown, hampering antiviral development. Here we determined the apo structure of monkeypox virus (MPXV) CorePro and the structure of CorePro in a complex with the inhibitor aloxistatin, a drug candidate for muscular dystrophy2. These structures show that CorePro forms a homodimer that features a unique 'dancing couple' fold. The catalytic intermediate state of CorePro was characterized by an aldehyde derivative from a natural substrate (I-G18). This derivative binds covalently to the catalytic Cys328, shifting the active site of the viral protease from a closed conformation in the apo form to a favourable open conformation upon substrate binding. On the basis of the CorePro-I-G18 complex, we designed a series of peptidomimetic inhibitors with a nitrile warhead, which could covalently anchor with the catalytic Cys328. These compounds inhibit CorePro with half-maximal inhibitory concentrations of 44.9-100.3 nM, and exhibit potent and broad anti-poxvirus activity. Our studies provide a basis for designing wide-spectrum inhibitors against poxvirus infections. |
| WOS关键词 | CRYSTAL-STRUCTURE ; 3-DIMENSIONAL STRUCTURE ; AMYLOID-BETA ; CATHEPSIN-B ; FOLD ; SPECIFICITY ; INHIBITOR ; UBIQUITIN ; E64D |
| 资助项目 | Shanghai Municipal Science and Technology Major Project[ZD2021CY001] ; Chinese Ministry of Education ; Lingang Laboratory[LG202101-01-07] ; National Natural Science Foundation of China[82130105] ; National Natural Science Foundation of China[82121005] ; National Natural Science Foundation of China[92253305] ; National Natural Science Foundation of China[81902063] ; Strategic Priority Research Program of Chinese Academy of Sciences[XDB0490000] ; Hubei Natural Science Foundation for Distinguished Young Scholars[2022CFA099] ; Chongqing Science and Technology Bureau[CSTB2024NSCQ-MSX0391] ; Chongqing Municipal Education Commission[KJQN202400433] ; Shanghai Rising Star Program[23QA1406400] ; China Postdoctoral Science Foundation[U22A20379] ; Joint Funds of the National Natural Science Foundation of China ; Shanghai Frontiers Science Center for Biomacromolecules and Precision Medicine of Shanghai Tech University ; Postdoctoral Fellowship Program ; [BX20240374] ; [2024M753225] |
| WOS研究方向 | Science & Technology - Other Topics |
| 语种 | 英语 |
| WOS记录号 | WOS:001511399500001 |
| 出版者 | NATURE PORTFOLIO |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/318386]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Wang, Wei; Zhang, Leike; Rao, Zihe; Liu, Hong; Yang, Haitao |
| 作者单位 | 1.Fudan Univ, Shanghai Inst Infect Dis & Biosecur, Sch Basic Med Sci, Shanghai, Peoples R China 2.Tsinghua Univ, Sch Med, Beijing, Peoples R China 3.Tsinghua Univ, Sch Life Sci, Lab Struct Biol, Beijing, Peoples R China 4.Nanjing Univ, Sch Life Sci, Dept Biotechnol & Pharmaceut Sci, State Key Lab Pharmaceut Biotechnol, Nanjing, Peoples R China 5.Cleveland Clin, Taussig Canc Ctr, Cleveland, OH USA 6.Asher Biotherapeut, South San Francisco, CA USA 7.Chinese Acad Sci, Shanghai Adv Res Inst, Natl Facil Prot Sci Shanghai, Shanghai, Peoples R China 8.Chongqing Med Univ, Coll Pharm, Chongqing, Peoples R China 9.Univ Chinese Acad Sci, Sch Pharmaceut Sci & Technol, Hangzhou Inst Adv Study, Hangzhou, Peoples R China 10.Guangzhou Lab, Guangzhou, Peoples R China |
| 推荐引用方式 GB/T 7714 | Gao, Yan,Xie, Xiong,Zhang, Xiaoyu,et al. Substrate recognition and cleavage mechanism of the monkeypox virus core protease[J]. NATURE,2025:29. |
| APA | Gao, Yan.,Xie, Xiong.,Zhang, Xiaoyu.,Cao, Junyuan.,Lan, Weiqi.,...&Yang, Haitao.(2025).Substrate recognition and cleavage mechanism of the monkeypox virus core protease.NATURE,29. |
| MLA | Gao, Yan,et al."Substrate recognition and cleavage mechanism of the monkeypox virus core protease".NATURE (2025):29. |
入库方式： OAI收割
来源：上海药物研究所
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