Crystal structure of SARS-CoV-2 nucleocapsid protein RNA binding domain reveals potential unique drug targeting sites

Sisi Kang; Mei Yang; Zhongsi Hong; Liping Zhang; Zhaoxia Huang; Xiaoxue Chen; Suhua He; Ziliang Zhou; Zhechong Zhou; Qiuyue Chen; Yan Yan; Changsheng Zhang; Hong Shan; Shoudeng Chen

doi:10.1016/j.apsb.2020.04.009

Crystal structure of SARS-CoV-2 nucleocapsid protein RNA binding domain reveals potential unique drug targeting sites

Acta Pharm Sin B. 2020 Jul;10(7):1228-1238. doi: 10.1016/j.apsb.2020.04.009. Epub 2020 Apr 20.

Authors

Sisi Kang¹, Mei Yang¹, Zhongsi Hong², Liping Zhang³, Zhaoxia Huang¹, Xiaoxue Chen¹, Suhua He¹, Ziliang Zhou¹, Zhechong Zhou¹, Qiuyue Chen¹, Yan Yan¹, Changsheng Zhang³, Hong Shan^{1

4

5}, Shoudeng Chen^{1

4

6}

Affiliations

¹ Molecular Imaging Center, Guangdong Provincial Key Laboratory of Biomedical Imaging, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China.
² Department of Infectious Diseases, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China.
³ Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Key Laboratory of Marine Materia Medica, Institution of South China Sea Ecology and Environmental Engineering, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 510301, China.
⁴ Guangdong Provincial Engineering Research Center of Molecular Imaging, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China.
⁵ Department of Interventional Medicine, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China.
⁶ Department of Experimental Medicine, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China.

Abstract

The outbreak of coronavirus disease (COVID-19) caused by SARS-CoV-2 virus continually lead to worldwide human infections and deaths. Currently, there is no specific viral protein-targeted therapeutics. Viral nucleocapsid protein is a potential antiviral drug target, serving multiple critical functions during the viral life cycle. However, the structural information of SARS-CoV-2 nucleocapsid protein remains unclear. Herein, we have determined the 2.7 Å crystal structure of the N-terminal RNA binding domain of SARS-CoV-2 nucleocapsid protein. Although the overall structure is similar as other reported coronavirus nucleocapsid protein N-terminal domain, the surface electrostatic potential characteristics between them are distinct. Further comparison with mild virus type HCoV-OC43 equivalent domain demonstrates a unique potential RNA binding pocket alongside the β-sheet core. Complemented by in vitro binding studies, our data provide several atomic resolution features of SARS-CoV-2 nucleocapsid protein N-terminal domain, guiding the design of novel antiviral agents specific targeting to SARS-CoV-2.

Keywords: Antiviral targeting site; COVID-19; Coronavirus; Crystal structure; Nucleocapsid protein; RNA binding domain; SARS-CoV-2.