4KXJ

Crystal structure of HCoV-OC43 N-NTD complexed with PJ34

Summary for 4KXJ

• Entry DOI: 10.2210/pdb4kxj/pdb
• Descriptor: Nucleoprotein, N~2~,N~2~-DIMETHYL-N~1~-(6-OXO-5,6-DIHYDROPHENANTHRIDIN-2-YL)GLYCINAMIDE (3 entities in total)
• Functional Keywords: hcov-oc43 n-ntd, rna binding protein, n-protein ligand
• Biological source: Human coronavirus (HCoV-OC43)
• Cellular location: Virion: Q6SA23
• Total number of polymer chains: 1
• Total formula weight: 15733.24

Authors

Lin, S.Y.,Hou, M.H. (deposition date: 2013-05-27, release date: 2014-05-28, Last modification date: 2024-03-20)

Primary citation

Lin, S.Y.,Liu, C.L.,Chang, Y.M.,Zhao, J.,Perlman, S.,Hou, M.H.
Structural basis for the identification of the N-terminal domain of coronavirus nucleocapsid protein as an antiviral target
J.Med.Chem., 57:2247-2257, 2014

PubMed Abstract: 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.

PubMed: 24564608
DOI: 10.1021/jm500089r

Experimental method

X-RAY DIFFRACTION (2.65 Å)