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: Lianying Jiao, Songying Ouyang, Mifang Liang, Fengfeng Niu, Neil Shaw, Wei Wu, Wei Ding, Cong Jin, Yao Peng, Yanping Zhu, Fushun Zhang, Tao Wang, Chuan Li, Xiaobing Zuo, Chi-Hao Luan, Dexin Li, Zhi-Jie Liu
• Journal: Journal of virology (J Virol) Vol. 87 Issue 12 Pg. 6829-39 (Jun 2013) ISSN: 1098-5514 [Electronic] United States
• PMID: 23576501 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Nucleocapsid Proteins
• RNA, Viral
• Suramin

Topics

• Amino Acid Sequence
• Animals
• Chlorocebus aethiops
• Crystallization
• Models, Molecular
• Molecular Sequence Data
• Nucleocapsid Proteins (chemistry, genetics, metabolism, therapeutic use)
• Phlebotomus Fever (drug therapy, virology)
• Phlebovirus (drug effects)
• Protein Folding
• RNA, Viral (genetics, metabolism)
• Sequence Analysis, DNA
• Structure-Activity Relationship
• Suramin (chemistry, metabolism, therapeutic use)
• Vero Cells
• Virus Replication (drug effects)