Structural and functional basis of low-affinity SAM/SAH-binding in the conserved MTase of the multi-segmented Alongshan virus distantly related to canonical unsegmented flaviviruses.
Alongshan virus (ALSV), a newly discovered member of unclassified Flaviviridae family, is able to infect humans. ALSV has a multi-segmented genome organization and is evolutionarily distant from canonical mono-segmented flaviviruses. The virus-encoded methyltransferase (MTase) plays an important rol...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2023-10-01
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| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1011694&type=printable |
| _version_ | 1827774667209834496 |
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| author | Hua Chen Sheng Lin Fanli Yang Zimin Chen Liyan Guo Jing Yang Xi Lin Lingling Wang Yanping Duan Ao Wen Xindan Zhang Yushan Dai Keqing Yin Xin Yuan Chongzhang Yu Yarong He Bin He Yu Cao Haohao Dong Jian Li Qi Zhao Quan Liu Guangwen Lu |
| author_facet | Hua Chen Sheng Lin Fanli Yang Zimin Chen Liyan Guo Jing Yang Xi Lin Lingling Wang Yanping Duan Ao Wen Xindan Zhang Yushan Dai Keqing Yin Xin Yuan Chongzhang Yu Yarong He Bin He Yu Cao Haohao Dong Jian Li Qi Zhao Quan Liu Guangwen Lu |
| author_sort | Hua Chen |
| collection | DOAJ |
| description | Alongshan virus (ALSV), a newly discovered member of unclassified Flaviviridae family, is able to infect humans. ALSV has a multi-segmented genome organization and is evolutionarily distant from canonical mono-segmented flaviviruses. The virus-encoded methyltransferase (MTase) plays an important role in viral replication. Here we show that ALSV MTase readily binds S-adenosyl-L-methionine (SAM) and S-adenosyl-L-homocysteine (SAH) but exhibits significantly lower affinities than canonical flaviviral MTases. Structures of ALSV MTase in the free and SAM/SAH-bound forms reveal that the viral enzyme possesses a unique loop-element lining side-wall of the SAM/SAH-binding pocket. While the equivalent loop in flaviviral MTases half-covers SAM/SAH, contributing multiple hydrogen-bond interactions; the pocket-lining loop of ALSV MTase is of short-length and high-flexibility, devoid of any physical contacts with SAM/SAH. Subsequent mutagenesis data further corroborate such structural difference affecting SAM/SAH-binding. Finally, we also report the structure of ALSV MTase bound with sinefungin, an SAM-analogue MTase inhibitor. These data have delineated the basis for the low-affinity interaction between ALSV MTase and SAM/SAH and should inform on antiviral drug design. |
| first_indexed | 2024-03-11T13:41:33Z |
| format | Article |
| id | doaj.art-9a374ab188f74bdbbce0d0cf34472fe8 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-03-11T13:41:33Z |
| publishDate | 2023-10-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-9a374ab188f74bdbbce0d0cf34472fe82023-11-02T11:49:11ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742023-10-011910e101169410.1371/journal.ppat.1011694Structural and functional basis of low-affinity SAM/SAH-binding in the conserved MTase of the multi-segmented Alongshan virus distantly related to canonical unsegmented flaviviruses.Hua ChenSheng LinFanli YangZimin ChenLiyan GuoJing YangXi LinLingling WangYanping DuanAo WenXindan ZhangYushan DaiKeqing YinXin YuanChongzhang YuYarong HeBin HeYu CaoHaohao DongJian LiQi ZhaoQuan LiuGuangwen LuAlongshan virus (ALSV), a newly discovered member of unclassified Flaviviridae family, is able to infect humans. ALSV has a multi-segmented genome organization and is evolutionarily distant from canonical mono-segmented flaviviruses. The virus-encoded methyltransferase (MTase) plays an important role in viral replication. Here we show that ALSV MTase readily binds S-adenosyl-L-methionine (SAM) and S-adenosyl-L-homocysteine (SAH) but exhibits significantly lower affinities than canonical flaviviral MTases. Structures of ALSV MTase in the free and SAM/SAH-bound forms reveal that the viral enzyme possesses a unique loop-element lining side-wall of the SAM/SAH-binding pocket. While the equivalent loop in flaviviral MTases half-covers SAM/SAH, contributing multiple hydrogen-bond interactions; the pocket-lining loop of ALSV MTase is of short-length and high-flexibility, devoid of any physical contacts with SAM/SAH. Subsequent mutagenesis data further corroborate such structural difference affecting SAM/SAH-binding. Finally, we also report the structure of ALSV MTase bound with sinefungin, an SAM-analogue MTase inhibitor. These data have delineated the basis for the low-affinity interaction between ALSV MTase and SAM/SAH and should inform on antiviral drug design.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1011694&type=printable |
| spellingShingle | Hua Chen Sheng Lin Fanli Yang Zimin Chen Liyan Guo Jing Yang Xi Lin Lingling Wang Yanping Duan Ao Wen Xindan Zhang Yushan Dai Keqing Yin Xin Yuan Chongzhang Yu Yarong He Bin He Yu Cao Haohao Dong Jian Li Qi Zhao Quan Liu Guangwen Lu Structural and functional basis of low-affinity SAM/SAH-binding in the conserved MTase of the multi-segmented Alongshan virus distantly related to canonical unsegmented flaviviruses. PLoS Pathogens |
| title | Structural and functional basis of low-affinity SAM/SAH-binding in the conserved MTase of the multi-segmented Alongshan virus distantly related to canonical unsegmented flaviviruses. |
| title_full | Structural and functional basis of low-affinity SAM/SAH-binding in the conserved MTase of the multi-segmented Alongshan virus distantly related to canonical unsegmented flaviviruses. |
| title_fullStr | Structural and functional basis of low-affinity SAM/SAH-binding in the conserved MTase of the multi-segmented Alongshan virus distantly related to canonical unsegmented flaviviruses. |
| title_full_unstemmed | Structural and functional basis of low-affinity SAM/SAH-binding in the conserved MTase of the multi-segmented Alongshan virus distantly related to canonical unsegmented flaviviruses. |
| title_short | Structural and functional basis of low-affinity SAM/SAH-binding in the conserved MTase of the multi-segmented Alongshan virus distantly related to canonical unsegmented flaviviruses. |
| title_sort | structural and functional basis of low affinity sam sah binding in the conserved mtase of the multi segmented alongshan virus distantly related to canonical unsegmented flaviviruses |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1011694&type=printable |
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