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Mechanism of NS2B-Mediated Activation of NS3pro in Dengue Virus: Molecular Dynamics Simulations and Bioassays

文献类型：期刊论文

作者Zuo, Zhili2; Liew, Oi Wah2; Chen, Gang2; Chong, Pek Ching Jenny2; Lee, Siew Hui2; Chen, Kaixian1; Jiang, Hualiang1; Puah, Chum Mok2; Zhu, Weiliang1
刊名JOURNAL OF VIROLOGY
出版日期2009-01-15
卷号83期号:2页码:1060-1070
ISSN号0022-538X
DOI10.1128/JVI.01325-08
文献子类Article
英文摘要The NS2B cofactor is critical for proteolytic activation of the flavivirus NS3 protease. To elucidate the mechanism involved in NS2B-mediated activation of NS3 protease, molecular dynamic simulation, principal component analysis, molecular docking, mutagenesis, and bioassay studies were carried out on both the dengue virus NS3pro and NS2B-NS3pro systems. The results revealed that the NS2B-NS3pro complex is more rigid than NS3pro alone due to its robust hydrogen bond and hydrophobic interaction networks within the complex. These potent networks lead to remodeling of the secondary and tertiary structures of the protease that facilitates cleavage sequence recognition and binding of substrates. The cofactor is also essential for proper domain motion that contributes to substrate binding. Hence, the NS2B cofactor plays a dual role in enzyme activation by facilitating the refolding of the NS3pro domain as well as being directly involved in substrate binding/ interactions. Kinetic analyses indicated for the first time that Glu92 and Asp50 in NS2B and Gln27, Gln35, and Arg54 in NS3pro may provide secondary interaction points for substrate binding. These new insights on the mechanistic contributions of the NS2B cofactor to NS3 activation may be utilized to refine current computer-based search strategies to raise the quality of candidate molecules identified as potent inhibitors against flaviviruses.
WOS关键词NONSTRUCTURAL PROTEINS ; GENUS FLAVIVIRUS ; SERINE-PROTEASE ; BETA-SECRETASE ; DOMAIN MOTIONS ; AMINO-ACIDS ; CLEAVAGE ; TYPE-2 ; NS2B ; REPLICATION
资助项目Singapore Polytechnic and the Singapore Totalisator Board Project[1127801-36-M103] ; 863 Program of China[2006AA02 Z336] ; international collaboration project of China[2007 DFB30370] ; 973 program of China[2004CB518901]
WOS研究方向Virology
语种英语
WOS记录号WOS:000262045000052
出版者AMER SOC MICROBIOLOGY
源URL[http://119.78.100.183/handle/2S10ELR8/279343]  
专题药物发现与设计中心
通讯作者Puah, Chum Mok
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China
2.Singapore Polytech, Ctr Biomed & Life Sci, Singapore 139651, Singapore;
推荐引用方式
GB/T 7714		 Zuo, Zhili,Liew, Oi Wah,Chen, Gang,et al. Mechanism of NS2B-Mediated Activation of NS3pro in Dengue Virus: Molecular Dynamics Simulations and Bioassays[J]. JOURNAL OF VIROLOGY,2009,83(2):1060-1070.
APA Zuo, Zhili.,Liew, Oi Wah.,Chen, Gang.,Chong, Pek Ching Jenny.,Lee, Siew Hui.,...&Zhu, Weiliang.(2009).Mechanism of NS2B-Mediated Activation of NS3pro in Dengue Virus: Molecular Dynamics Simulations and Bioassays.JOURNAL OF VIROLOGY,83(2),1060-1070.
MLA Zuo, Zhili,et al."Mechanism of NS2B-Mediated Activation of NS3pro in Dengue Virus: Molecular Dynamics Simulations and Bioassays".JOURNAL OF VIROLOGY 83.2(2009):1060-1070.

入库方式： OAI收割

来源：上海药物研究所

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