title: Structure of severe fever with thrombocytopenia syndrome virus nucleocapsid protein in complex with suramin reveals therapeutic potential.
abstract: Severe fever with thrombocytopenia syndrome is an emerging infectious disease caused by a novel bunyavirus (SFTSV). Lack of vaccines and inadequate therapeutic treatments have made the spread of the virus a global concern. Viral nucleocapsid protein (N) is essential for its transcription and replication. Here, we present the crystal structures of N from SFTSV and its homologs from Buenaventura (BUE) and Granada (GRA) viruses. The structures reveal that phleboviral N folds into a compact core domain and an extended N-terminal arm that mediates oligomerization, such as tetramer, pentamer, and hexamer of N assemblies. Structural superimposition indicates that phleboviral N adopts a conserved architecture and uses a similar RNA encapsidation strategy as that of RVFV-N. The RNA binding cavity runs along the inner edge of the ring-like assembly. A triple mutant of SFTSV-N, R64D/K67D/K74D, almost lost its ability to bind RNA in vitro, is deficient in its ability to transcribe and replicate. Structural studies of the mutant reveal that both alterations in quaternary assembly and the charge distribution contribute to the loss of RNA binding. In the screening of inhibitors Suramin was identified to bind phleboviral N specifically. The complex crystal structure of SFTSV-N with Suramin was refined to a 2.30-Å resolution. Suramin was found sitting in the putative RNA binding cavity of SFTSV-N. The inhibitory effect of Suramin on SFTSV replication was confirmed in Vero cells. Therefore, a common Suramin-based therapeutic approach targeting SFTSV-N and its homologs could be developed for containing phleboviral outbreaks.
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Lianying
authors.initials: L
authors.lastname: Jiao
authors.forename: Songying
authors.initials: S
authors.lastname: Ouyang
authors.forename: Mifang
authors.initials: M
authors.lastname: Liang
authors.forename: Fengfeng
authors.initials: F
authors.lastname: Niu
authors.forename: Neil
authors.initials: N
authors.lastname: Shaw
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.forename: Wei
authors.initials: W
authors.lastname: Ding
authors.forename: Cong
authors.initials: C
authors.lastname: Jin
authors.forename: Yao
authors.initials: Y
authors.lastname: Peng
authors.forename: Yanping
authors.initials: Y
authors.lastname: Zhu
authors.forename: Fushun
authors.initials: F
authors.lastname: Zhang
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Chuan
authors.initials: C
authors.lastname: Li
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Zuo
authors.forename: Chi-Hao
authors.initials: CH
authors.lastname: Luan
authors.forename: Dexin
authors.initials: D
authors.lastname: Li
authors.forename: Zhi-Jie
authors.initials: ZJ
authors.lastname: Liu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002522:Chlorocebus aethiops; D003460:Crystallization; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019590:Nucleocapsid Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D010217:Phlebotomus Fever / Q000188:drug therapy* / Q000821:virology; D016856:Phlebovirus / Q000187:drug effects*; D017510:Protein Folding; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA; D013329:Structure-Activity Relationship; D013498:Suramin / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use*; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019590:Nucleocapsid Proteins; D012367:RNA, Viral; D013498:Suramin