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Cryo-EM structures of African swine fever virus topoisomerase

Type II topoisomerases ubiquitously exist in cellular organisms, where they play an essential role in resolving the topological problems of DNA. The viral type II topoisomerase encoded by the African swine fever virus (ASFV) is critical for viral replication and infection, thus representing an attra...

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Autores principales: Zhao, Yan, Kuang, Wenhua, An, Qiyin, Li, Jinyue, Wang, Yong, Deng, Zengqin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10653817/
https://www.ncbi.nlm.nih.gov/pubmed/37610250
http://dx.doi.org/10.1128/mbio.01228-23
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author Zhao, Yan
Kuang, Wenhua
An, Qiyin
Li, Jinyue
Wang, Yong
Deng, Zengqin
author_facet Zhao, Yan
Kuang, Wenhua
An, Qiyin
Li, Jinyue
Wang, Yong
Deng, Zengqin
author_sort Zhao, Yan
collection PubMed
description Type II topoisomerases ubiquitously exist in cellular organisms, where they play an essential role in resolving the topological problems of DNA. The viral type II topoisomerase encoded by the African swine fever virus (ASFV) is critical for viral replication and infection, thus representing an attractive target for antiviral drug development. Here we report two cryo-EM structures of ASFV topoisomerase P1192R in distinct conformations at an overall resolution of 3.16 Å and 3.13 Å, respectively. P1192R assembles as a homodimer with the C-gate formed by the coiled-coil domain adopting a closed or open conformation before reaction, providing the first visual evidence for the dynamic motions of the C-gate of type II topoisomerase. Comparative structural comparisons of eukaryotic homologs and P1192R reveal the unique structural features of P1192R, including the active site configuration, a flexible loop in the TOPRIM domain, an additionally inserted α-helix in the tower domain, and a pin-like structure in the C-terminal coiled-coil domain, which are important for enzyme activity and protein folding. These findings provide important insights into the structure and function of viral topoisomerases and may guide the efficient development of anti-ASFV drugs. Moreover, our study also offers structural evidence to support the scenario of the viral origin of eukaryotic type IIA topoisomerases. IMPORTANCE: African swine fever virus (ASFV) is a highly contagious virus that causes lethal hemorrhagic diseases known as African swine fever (ASF) with a case fatality rate of 100%. There is an urgent need to develop anti-ASFV drugs. We determine the first high-resolution structures of viral topoisomerase ASFV P1192R in both the closed and open C-gate forms. P1192R shows a similar overall architecture with eukaryotic and prokaryotic type II topoisomerases, which have been successful targets of many antimicrobials and anticancer drugs, with the most similarity to yeast topo II. P1192R also exhibits differences in the details of active site configuration, which are important to enzyme activity. These two structures offer useful structural information for antiviral drug design and provide structural evidence to support that eukaryotic type IIA topoisomerase likely originated from horizontal gene transfer from the virus.
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spelling pubmed-106538172023-08-23 Cryo-EM structures of African swine fever virus topoisomerase Zhao, Yan Kuang, Wenhua An, Qiyin Li, Jinyue Wang, Yong Deng, Zengqin mBio Research Article Type II topoisomerases ubiquitously exist in cellular organisms, where they play an essential role in resolving the topological problems of DNA. The viral type II topoisomerase encoded by the African swine fever virus (ASFV) is critical for viral replication and infection, thus representing an attractive target for antiviral drug development. Here we report two cryo-EM structures of ASFV topoisomerase P1192R in distinct conformations at an overall resolution of 3.16 Å and 3.13 Å, respectively. P1192R assembles as a homodimer with the C-gate formed by the coiled-coil domain adopting a closed or open conformation before reaction, providing the first visual evidence for the dynamic motions of the C-gate of type II topoisomerase. Comparative structural comparisons of eukaryotic homologs and P1192R reveal the unique structural features of P1192R, including the active site configuration, a flexible loop in the TOPRIM domain, an additionally inserted α-helix in the tower domain, and a pin-like structure in the C-terminal coiled-coil domain, which are important for enzyme activity and protein folding. These findings provide important insights into the structure and function of viral topoisomerases and may guide the efficient development of anti-ASFV drugs. Moreover, our study also offers structural evidence to support the scenario of the viral origin of eukaryotic type IIA topoisomerases. IMPORTANCE: African swine fever virus (ASFV) is a highly contagious virus that causes lethal hemorrhagic diseases known as African swine fever (ASF) with a case fatality rate of 100%. There is an urgent need to develop anti-ASFV drugs. We determine the first high-resolution structures of viral topoisomerase ASFV P1192R in both the closed and open C-gate forms. P1192R shows a similar overall architecture with eukaryotic and prokaryotic type II topoisomerases, which have been successful targets of many antimicrobials and anticancer drugs, with the most similarity to yeast topo II. P1192R also exhibits differences in the details of active site configuration, which are important to enzyme activity. These two structures offer useful structural information for antiviral drug design and provide structural evidence to support that eukaryotic type IIA topoisomerase likely originated from horizontal gene transfer from the virus. American Society for Microbiology 2023-08-23 /pmc/articles/PMC10653817/ /pubmed/37610250 http://dx.doi.org/10.1128/mbio.01228-23 Text en Copyright © 2023 Zhao et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Zhao, Yan
Kuang, Wenhua
An, Qiyin
Li, Jinyue
Wang, Yong
Deng, Zengqin
Cryo-EM structures of African swine fever virus topoisomerase
title Cryo-EM structures of African swine fever virus topoisomerase
title_full Cryo-EM structures of African swine fever virus topoisomerase
title_fullStr Cryo-EM structures of African swine fever virus topoisomerase
title_full_unstemmed Cryo-EM structures of African swine fever virus topoisomerase
title_short Cryo-EM structures of African swine fever virus topoisomerase
title_sort cryo-em structures of african swine fever virus topoisomerase
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10653817/
https://www.ncbi.nlm.nih.gov/pubmed/37610250
http://dx.doi.org/10.1128/mbio.01228-23
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