Characterization of the Heptad Repeat Regions, HR1 and HR2, and Design of a Fusion Core Structure Model of the Spike Protein from Severe Acute Respiratory Syndrome (SARS) Coronavirus

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• 作者：Yanhui Xu ; Jieqing Zhu ; Yiwei Liu ; Zhiyong Lou ; Fang Yuan ; Yueyong Liu ; David K. Cole ; Ling Ni ; Nan Su ; Lan Qin ; Xu Li ; Zhihong Bai ; John I. Bell ; Hai Pang ; Po Tien ; George F. Gao ; and Zihe Rao
• 刊名：Biochemistry
• 出版年：2004
• 出版时间：November 9, 2004
• 年：2004
• 卷：43
• 期：44
• 页码：14064 - 14071
• 全文大小：439K
• 年卷期：v.43,no.44(November 9, 2004)
• ISSN：1520-4995

文摘

Severe acute respiratory syndrome coronavirus (SARS-CoV) is a newly emergent virusresponsible for a worldwide epidemic in 2003. The coronavirus spike proteins belong to class I fusionproteins, and are characterized by the existence of two heptad repeat (HR) regions, HR1 and HR2. TheHR1 region in coronaviruses is predicted to be considerably longer than that in other type I virus fusionproteins. Therefore the exact binding sequence to HR2 from the HR1 is not clear. In this study, we definedthe region of HR1 that binds to HR2 by a series of biochemical and biophysical measures. Subsequentlythe defined HR1 (902-952) and HR2 (1145-1184) chains, which are different from previously definedbinding regions, were linked together by a flexible linker to form a single-chain construct, 2-Helix. Thisprotein was expressed in Escherichia coli and forms a typical six-helix coiled coil bundle. Highly conservedHR regions between mouse hepatitis virus (MHV) and SARS-CoV spike proteins suggest a similar three-dimensional structure for the two fusion cores. Here, we constructed a homology model for SARScoronavirus fusion core based on our biochemical analysis and determined the MHV fusion core structure.We also propose an important target site for fusion inhibitor design and several strategies, which havebeen successfully used in fusion inhibitor design for human immunodeficiency virus (HIV), for the treatmentof SARS infection.