globalchange  > 气候变化与战略
DOI: 10.1073/pnas.1900656116
论文题名:
Structural insights into RNA recognition by the Chikungunya virus nsP2 helicase
作者: Law Y.-S.; Utt A.; Tan Y.B.; Zheng J.; Wang S.; Chen M.W.; Griffin P.R.; Merits A.; Luo D.
刊名: Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
出版年: 2019
卷: 116, 期:19
起始页码: 9558
结束页码: 9567
语种: 英语
英文关键词: Alphavirus ; ATP hydrolysis ; Chikungunya virus ; Nonstructural protein 2 ; Superfamily 1 helicase
Scopus关键词: adenosine diphosphate ; adenosine triphosphatase ; RNA helicase ; adenosine diphosphate tetrafluoroaluminate ; organometallic compound ; RNA helicase ; viral protein ; virus RNA ; Alphavirus ; amino acid substitution ; amino terminal sequence ; Article ; binding affinity ; Chikungunya virus ; controlled study ; crystal structure ; enzyme activity ; enzyme structure ; gene mutation ; hydrophobicity ; nonhuman ; priority journal ; protein binding ; protein family ; protein folding ; protein interaction ; protein motif ; RNA binding ; RNA recognition motif ; RNA synthesis ; RNA transcription ; RNA virus ; structure analysis ; U2OS cell line ; virus genome ; virus replication ; virus virulence ; biosynthesis ; chemistry ; Chikungunya virus ; metabolism ; protein domain ; Adenosine Diphosphate ; Chikungunya virus ; Organometallic Compounds ; Protein Domains ; RNA Helicases ; RNA, Viral ; Viral Proteins
英文摘要: Chikungunya virus (CHIKV) is transmitted to humans through mosquitoes and causes Chikungunya fever. Nonstructural protein 2 (nsP2) exhibits the protease and RNA helicase activities that are required for viral RNA replication and transcription. Unlike for the C-terminal protease, the structure of the N-terminal RNA helicase (nsP2h) has not been determined. Here, we report the crystal structure of the nsP2h bound to the conserved 3′-end 14 nucleotides of the CHIKV genome and the nonhydrolyzable transition-state nucleotide analog ADP-AlF4. Overall, the structural analysis revealed that nsP2h adopts a uniquely folded N-terminal domain followed by a superfamily 1 RNA helicase fold. The conserved helicase motifs establish polar contacts with the RNA backbone. There are three hydrophobic residues (Y161, F164, and F287) which form stacking interactions with RNA bases and thereby bend the RNA backbone. An F287A substitution that disrupted these stacking interactions increased the basal ATPase activity but decreased the RNA binding affinity. Furthermore, the F287A substitution reduced viral infectivity by attenuating subgenomic RNA synthesis. Replication of the mutant virus was restored by pseudoreversion (A287V) or adaptive mutations in the RecA2 helicase domain (T358S or V410I). Y161A and/or F164A substitutions, which were designed to disrupt the interactions with the RNA molecule, did not affect the ATPase activity but completely abolished the replication and transcription of viral RNA and the infectivity of CHIKV. Our study sheds light on the roles of the RNA helicase region in viral replication and provides insights that might be applicable to alphaviruses and other RNA viruses in general. © 2019 National Academy of Sciences. All rights reserved.
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资源类型: 期刊论文
标识符: http://119.78.100.158/handle/2HF3EXSE/163558
Appears in Collections:气候变化与战略

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作者单位: Law, Y.-S., Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, 636921, Singapore, NTU Institute of Structural Biology, Nanyang Technological University, Singapore, 636921, Singapore; Utt, A., Institute of Technology, University of Tartu, Tartu, 50411, Estonia; Tan, Y.B., Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, 636921, Singapore, NTU Institute of Structural Biology, Nanyang Technological University, Singapore, 636921, Singapore; Zheng, J., Department of Molecular Medicine, Scripps Research Institute, Jupiter, FL 33458, United States, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; Wang, S., Institute of Technology, University of Tartu, Tartu, 50411, Estonia; Chen, M.W., NTU Institute of Structural Biology, Nanyang Technological University, Singapore, 636921, Singapore, School of Biological Sciences, Nanyang Technological University, Singapore, 637551, Singapore; Griffin, P.R., Department of Molecular Medicine, Scripps Research Institute, Jupiter, FL 33458, United States; Merits, A., Institute of Technology, University of Tartu, Tartu, 50411, Estonia; Luo, D., Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, 636921, Singapore, NTU Institute of Structural Biology, Nanyang Technological University, Singapore, 636921, Singapore

Recommended Citation:
Law Y.-S.,Utt A.,Tan Y.B.,et al. Structural insights into RNA recognition by the Chikungunya virus nsP2 helicase[J]. Proceedings of the National Academy of Sciences of the United States of America,2019-01-01,116(19)
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