+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Structural basis for the identification of the N-terminal domain of coronavirus nucleocapsid protein as an antiviral target



Structural basis for the identification of the N-terminal domain of coronavirus nucleocapsid protein as an antiviral target



Journal of Medicinal Chemistry 57(6): 2247-2257



Coronaviruses (CoVs) cause numerous diseases, including Middle East respiratory syndrome and severe acute respiratory syndrome, generating significant health-related and economic consequences. CoVs encode the nucleocapsid (N) protein, a major structural protein that plays multiple roles in the virus replication cycle and forms a ribonucleoprotein complex with the viral RNA through the N protein's N-terminal domain (N-NTD). Using human CoV-OC43 (HCoV-OC43) as a model for CoV, we present the 3D structure of HCoV-OC43 N-NTD complexed with ribonucleoside 5'-monophosphates to identify a distinct ribonucleotide-binding pocket. By targeting this pocket, we identified and developed a new coronavirus N protein inhibitor, N-(6-oxo-5,6-dihydrophenanthridin-2-yl)(N,N-dimethylamino)acetamide hydrochloride (PJ34), using virtual screening; this inhibitor reduced the N protein's RNA-binding affinity and hindered viral replication. We also determined the crystal structure of the N-NTD-PJ34 complex. On the basis of these findings, we propose guidelines for developing new N protein-based antiviral agents that target CoVs.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 055948758

Download citation: RISBibTeXText

PMID: 24564608

DOI: 10.1021/jm500089r


Related references

Oligomerization of the carboxyl terminal domain of the human coronavirus 229E nucleocapsid protein. Febs Letters 587(2): 120-127, 2013

A major determinant for membrane protein interaction localizes to the carboxy-terminal domain of the mouse coronavirus nucleocapsid protein. Journal of Virology 79(21): 13285-13297, 2005

Crystallographic analysis of the N-terminal domain of Middle East respiratory syndrome coronavirus nucleocapsid protein. Acta Crystallographica. Section F Structural Biology Communications 71(Pt 8): 977-980, 2015

The nucleocapsid protein of the SARS coronavirus is capable of self-association through a C-terminal 209 amino acid interaction domain. Biochemical and Biophysical Research Communications 317(4): 1030-1036, 2004

Crystallization and preliminary X-ray diffraction analysis of the N-terminal domain of human coronavirus OC43 nucleocapsid protein. Acta Crystallographica. Section F Structural Biology and Crystallization Communications 66(Pt 7): 815-818, 2010

Characterization of Two Monoclonal Antibodies That Recognize Linker Region and Carboxyl Terminal Domain of Coronavirus Nucleocapsid Protein. Plos one 11(9): E0163920, 2016

The nucleocapsid protein of coronavirus infectious bronchitis virus: crystal structure of its N-terminal domain and multimerization properties. Structure 13(12): 1859-1868, 2005

Solution structure of the c-terminal dimerization domain of SARS coronavirus nucleocapsid protein solved by the SAIL-NMR method. Journal of Molecular Biology 380(4): 608-622, 2008

Recombinant severe acute respiratory syndrome (SARS) coronavirus nucleocapsid protein forms a dimer through its C-terminal domain. Journal of Biological Chemistry 280(24): 23280-6, 2005

X-ray structures of the N- and C-terminal domains of a coronavirus nucleocapsid protein: implications for nucleocapsid formation. Journal of Virology 80(13): 6612-6620, 2006

Identification of a receptor-binding domain in the S protein of the novel human coronavirus Middle East respiratory syndrome coronavirus as an essential target for vaccine development. Journal of Virology 87(17): 9939-9942, 2013

Immunoreactivity characterisation of the three structural regions of the human coronavirus OC43 nucleocapsid protein by Western blot: implications for the diagnosis of coronavirus infection. Journal of Virological Methods 187(2): 413-420, 2013

Severe acute respiratory syndrome coronavirus nucleocapsid protein confers ability to efficiently produce virus-like particles when substituted for the human immunodeficiency virus nucleocapsid domain. Journal of Biomedical Science 15(6): 719-729, 2008

The carboxy-terminal domain of Sendai virus nucleocapsid protein is involved in complex formation between phosphoprotein and nucleocapsid-like particles. Virology 204(2): 770-776, 1994

Investigations into the amino-terminal domain of the respiratory syncytial virus nucleocapsid protein reveal elements important for nucleocapsid formation and interaction with the phosphoprotein. Virology 307(1): 3-53, 2003