Academic Journal
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: | 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. |
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| Authors: | 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 |
| Source: | PLoS Pathogens, Vol 19, Iss 10, p e1011694 (2023) |
| Publisher Information: | Public Library of Science (PLoS), 2023. |
| Publication Year: | 2023 |
| Collection: | LCC:Immunologic diseases. Allergy LCC:Biology (General) |
| Subject Terms: | Immunologic diseases. Allergy, RC581-607, Biology (General), QH301-705.5 |
| More Details: | 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. |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 1553-7366 1553-7374 |
| Relation: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1011694&type=printable; https://doaj.org/toc/1553-7366; https://doaj.org/toc/1553-7374 |
| DOI: | 10.1371/journal.ppat.1011694&type=printable |
| DOI: | 10.1371/journal.ppat.1011694 |
| Access URL: | https://doaj.org/article/9a374ab188f74bdbbce0d0cf34472fe8 |
| Accession Number: | edsdoj.9a374ab188f74bdbbce0d0cf34472fe8 |
| Database: | Directory of Open Access Journals |
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| ISSN: | 15537366 15537374 |
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| DOI: | 10.1371/journal.ppat.1011694&type=printable |
| Published in: | PLoS Pathogens |
| Language: | English |