Structural basis for difunctional mechanism of m-AMSA against African swine fever virus pP1192R
The African swine fever virus (ASFV) type II topoisomerase (Topo II), pP1192R, is the only known Topo II expressed by mammalian viruses and is essential for ASFV replication in the host cytoplasm. Herein, we report the structures of pP1192R in various enzymatic stages using both X-ray crystallography and single-particle cryo-electron microscopy. Our data structurally define the pP1192R-modulated DNA topology changes. By presenting the A2+-like metal ion at the pre-cleavage site, the pP1192R-DNA-m-AMSA complex structure provides support for the classical two-metal mechanism in Topo II-mediated DNA cleavage and a better explanation for nucleophile formation. The unique inhibitor selectivity of pP1192R and the difunctional mechanism of pP1192R inhibition by m-AMSA highlight the specificity of viral Topo II in the poison binding site. Altogether, this study provides the information applicable to the development of a pP1192R-targeting anti-ASFV strategy.
Authors
- George F. Gao (ORCID: https://orcid.org/0000-0002-3869-615X)
- Guorui Peng
- Han Wang (ORCID: https://orcid.org/0000-0003-0865-8651)
- Jianxun Qi
- Lian‐Feng Li (ORCID: https://orcid.org/0000-0001-9653-5533)
- Junqing Sun
- Su Li (ORCID: https://orcid.org/0000-0002-5845-4617)
- Lifeng Fu (ORCID: https://orcid.org/0000-0003-0431-5424)
- Hua-Ji Qiu (ORCID: https://orcid.org/0000-0001-5791-0812)
- Yanli Wang (ORCID: https://orcid.org/0000-0002-5969-1745)
- Yanjin Wang (ORCID: https://orcid.org/0009-0005-1484-2537)
- Xiaomei Li (ORCID: https://orcid.org/0000-0001-6505-3363)
- Ruili Liu (ORCID: https://orcid.org/0000-0002-8757-1409)
- Jiaqi Ran
- Erqi Pang
- Sheng Liu
- Xiao Qu (ORCID: https://orcid.org/0000-0001-8482-3116)
- Meilin Li
- Yingxian Cheng
Institutions
- Liaoning University (CN)
- Shanxi Agricultural University (CN)
- Chinese Academy of Sciences (CN)
- Peking University (CN)
- Southern University of Science and Technology (CN)
- Shanxi Academy of Building Research (CN)
- Czech Academy of Sciences, Institute of Microbiology (CZ)
- China Institute of Veterinary Drug Control (CN)
- Chinese Academy of Agricultural Sciences (CN)
- Beijing Academy of Science and Technology (CN)
- Henan Agricultural University (CN)
- Harbin Veterinary Research Institute (CN)
Publication Details
- Journal
- Nucleic Acids Research
- Published
- 2024-08-21
- DOI
- https://doi.org/10.1093/nar/gkae703
- Citations
- 3
- Primary Topic
- Plant Virus Research Studies
- Type
- article
- Field-Weighted Citation Impact
- 1.80
Funders
- National Natural Science Foundation of China
- Peking University
- National Key Research and Development Program of China
- Fundamental Research Funds for the Central Universities