Structural Insight into Molecular Inhibitory Mechanism of InsP(6) on African Swine Fever Virus mRNA-Decapping Enzyme g5Rp

doi:10.1128/jvi.01905-21

	Structural Insight into Molecular Inhibitory Mechanism of InsP(6) on African Swine Fever Virus mRNA-Decapping Enzyme g5Rp
	Yang, Yan 1,2,3; Zhang, Changhui 1,2,3; Li, Xuehui 1,2,3; Li, Li 1,2,3; Chen, Yanjuan 1,2,3; Yang, Xin 4; Zhao, Yao5,6 ; Chen, Cheng 7; Wang, Wei 4; Zhong, Zhihui 1,2,3; Yang, Cheng 1,2,3; Huang, Zhen 8; Su, Dan 1,2,3,9
	2022-05-25
发表期刊	JOURNAL OF VIROLOGY (IF:4.0[JCR-2023],4.0[5-Year])
ISSN	0022-538X
EISSN	1098-5514
发表状态	已发表
DOI	10.1128/jvi.01905-21
摘要	["ASF is a highly contagious hemorrhagic viral disease in domestic pigs which causes high mortality. Currently, there are still no effective vaccines or specific drugs available against this particular virus.","Removal of 5 ' cap on cellular mRNAs by the African swine fever virus (ASFV) decapping enzyme g5R protein (g5Rp) is beneficial to viral gene expression during the early stages of infection. As the only nucleoside diphosphate-linked moiety X (Nudix) decapping enzyme encoded in the ASFV genome, g5Rp works in both the degradation of cellular mRNA and the hydrolyzation of the diphosphoinositol polyphosphates. Here, we report the structures of dimeric g5Rp and its complex with inositol hexakisphosphate (InsP(6)). The two g5Rp protomers interact head to head to form a dimer, and the dimeric interface is formed by extensive polar and nonpolar interactions. Each protomer is composed of a unique N-terminal helical domain and a C-terminal classic Nudix domain. As g5Rp is an mRNA-decapping enzyme, we identified key residues, including K-8, K-94, K-95, K-98, K-175, R-221, and K-243 located on the substrate RNA binding interfaces of g5Rp which are important to RNA binding and decapping enzyme activity. Furthermore, the g5Rp-mediated mRNA decapping was inhibited by InsP(6). The g5Rp-InsP(6) complex structure showed that the InsP(6) molecules occupy the same regions that primarily mediate g5Rp-RNA interaction, elucidating the roles of InsP(6) in the regulation of the viral decapping activity of g5Rp in mRNA degradation. Collectively, these results provide the structural basis of interaction between RNA and g5Rp and highlight the inhibitory mechanism of InsP(6) on mRNA decapping by g5Rp. IMPORTANCE ASF is a highly contagious hemorrhagic viral disease in domestic pigs which causes high mortality. Currently, there are still no effective vaccines or specific drugs available against this particular virus. The protein g5Rp is the only viral mRNA-decapping enzyme, playing an essential role in the machinery assembly of mRNA regulation and translation initiation. In this study, we solved the crystal structures of g5Rp dimer and complex with InsP(6). Structure-based mutagenesis studies revealed critical residues involved in a candidate RNA binding region, which also play pivotal roles in complex with InsP(6). Notably, InsP(6) can inhibit g5Rp activity by competitively blocking the binding of substrate mRNA to the enzyme. Our structure-function studies provide the basis for potential anti-ASFV inhibitor designs targeting the critical enzyme."]
关键词	g5Rp ASFV mRNA-decapping enzyme Nudix hydrolases InsP(6)
URL	查看原文
收录类别	SCI ; SCIE
语种	英语
资助项目	National Key Research and Development Program of China[2017YFA0505903] ; National Natural Science Foundation of China[31370735,31670737] ; Science and Technology Department of the Tianjin Foundation[19YFZCSN00470] ; Special Research Fund on COVID-19 of Sichuan Province[2020YFS0010] ; West China Hospital, Sichuan University[HX-2019-nCoV-044]
WOS研究方向	Virology
WOS类目	Virology
WOS记录号	WOS:000789427100001
出版者	AMER SOC MICROBIOLOGY
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/180885
专题	免疫化学研究所_特聘教授组_饶子和组生命科学与技术学院
通讯作者	Su, Dan
作者单位	1.Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Chengdu, Sichuan, Peoples R China 2.Sichuan Univ, West China Hosp, Canc Ctr, Chengdu, Sichuan, Peoples R China 3.Collaborat Innovat Ctr Biotherapy, Chengdu, Sichuan, Peoples R China 4.Chongqing Med Univ, Inst Life Sci, Chongqing, Peoples R China 5.ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai, Peoples R China 6.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China 7.Tianjin Univ, Sch Life Sci, Tianjin, Peoples R China 8.Sichuan Univ, Coll Life Sci, Chengdu, Peoples R China 9.Tianjin Int Joint Acad Biotechnol & Med, Tianjin, Peoples R China
推荐引用方式 GB/T 7714	Yang, Yan,Zhang, Changhui,Li, Xuehui,et al. Structural Insight into Molecular Inhibitory Mechanism of InsP(6) on African Swine Fever Virus mRNA-Decapping Enzyme g5Rp[J]. JOURNAL OF VIROLOGY,2022.
APA	Yang, Yan.,Zhang, Changhui.,Li, Xuehui.,Li, Li.,Chen, Yanjuan.,...&Su, Dan.(2022).Structural Insight into Molecular Inhibitory Mechanism of InsP(6) on African Swine Fever Virus mRNA-Decapping Enzyme g5Rp.JOURNAL OF VIROLOGY.
MLA	Yang, Yan,et al."Structural Insight into Molecular Inhibitory Mechanism of InsP(6) on African Swine Fever Virus mRNA-Decapping Enzyme g5Rp".JOURNAL OF VIROLOGY (2022).