Structures of the SARS‐CoV‐2 nucleocapsid and their perspectives for drug design

COVID‐19, caused by SARS‐CoV‐2, has resulted in severe and unprecedented economic and social disruptions in the world. Nucleocapsid (N) protein, which is the major structural component of the virion and is involved in viral replication, assembly and immune regulation, plays key roles in the viral li...

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Veröffentlicht in:The EMBO journal Jg. 39; H. 20; S. e105938 - n/a
Hauptverfasser: Peng, Ya, Du, Ning, Lei, Yuqing, Dorje, Sonam, Qi, Jianxun, Luo, Tingrong, Gao, George F, Song, Hao
Format: Journal Article
Sprache:Englisch
Veröffentlicht: London Nature Publishing Group UK 15.10.2020
Springer Nature B.V
John Wiley and Sons Inc
Schlagworte:
2019‐nCoV
Antigenic characteristics
Antigens
Antiviral agents
Antiviral Agents - pharmacology
Antiviral drugs
antivirals
Assembly
Betacoronavirus - chemistry
Betacoronavirus - drug effects
Binding sites
Blocking
Charge distribution
Coronavirus Nucleocapsid Proteins
COVID-19
Crystal structure
Crystallography, X-Ray
Diagnostic systems
dimerization
Domains
Drug Delivery Systems
Drug Design
Drug development
Drug discovery
EMBO23
EMBO40
Humans
Immunoregulation
Life cycles
Models, Molecular
N protein
nucleocapsid
Nucleocapsid Proteins - chemistry
Nucleocapsid Proteins - drug effects
Nucleocapsids
Oligomerization
Phosphoproteins
Protein Conformation
Protein Domains
Protein structure
Proteins
Recombinant Proteins - chemistry
Ribonucleic acid
RNA
RNA binding
SARS-CoV-2
Severe acute respiratory syndrome
Severe acute respiratory syndrome coronavirus 2
Therapeutic targets
Viral diseases
Virions
nucleocapsid
dimerization
antivirals
2019‐nCoV
RNA binding
2019-nCoV
ISSN:0261-4189, 1460-2075, 1460-2075
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Zusammenfassung:COVID‐19, caused by SARS‐CoV‐2, has resulted in severe and unprecedented economic and social disruptions in the world. Nucleocapsid (N) protein, which is the major structural component of the virion and is involved in viral replication, assembly and immune regulation, plays key roles in the viral life cycle. Here, we solved the crystal structures of the N‐ and C‐terminal domains (N‐NTD and N‐CTD) of SARS‐CoV‐2 N protein, at 1.8 and 1.5 Å resolution, respectively. Both structures show conserved features from other CoV N proteins. The binding sites targeted by small molecules against HCoV‐OC43 and MERS‐CoV, which inhibit viral infection by blocking the RNA‐binding activity or normal oligomerization of N protein, are relatively conserved in our structure, indicating N protein is a promising drug target. In addition, certain areas of N‐NTD and N‐CTD display distinct charge distribution patterns in SARS‐CoV‐2, which may alter the RNA‐binding modes. The specific antigenic characteristics are critical for developing specific immune‐based rapid diagnostic tests. Our structural information can aid in the discovery and development of antiviral inhibitors against SARS‐CoV‐2 in the future. Synopsis SARS‐CoV‐2 has emerged as a major health concern, and nucleocapsid (N) is a potential target for the development of antivirals to block ribonucleoprotein assembly. Here, the high‐resolution crystal structures of the N‐ and C‐terminal domains of SARS‐CoV‐2 N protein are reported, which provide a basis for antiviral drug discovery. Structures of the N‐ and C‐terminal domains (N‐NTD and N‐CTD) of SARS‐CoV-2 N protein, at 1.8 and 1.5 Å resolution, respectively. Both N‐NTD and N‐CTD display both conserved and specific features patterns in SARS‐CoV-2. Identification of features on N‐NTD that lend to structure‐based drug discovery. Graphical Abstract High‐resolution structures of the N‐ and C‐terminal domains of SARS‐CoV‐2 N protein reveal conserved as well as unique features compared to other coronavirus N proteins.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:0261-4189
1460-2075
1460-2075
DOI:10.15252/embj.2020105938