8J6X

Crystal structure of SARS-CoV2 N-NTD complexed with 5-Benzyloxygramine derivative (P3-8)

Summary for 8J6X

• Entry DOI: 10.2210/pdb8j6x/pdb
• Descriptor: Nucleoprotein, ~{N}-methyl-~{N}-[(5-phenylmethoxy-1~{H}-indol-3-yl)methyl]propan-1-amine (3 entities in total)
• Functional Keywords: severe acute respiratory syndrome coronavirus 2 nucleocapsid protein 5-benzyloxygramine, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 4
• Total formula weight: 68520.54

Authors

Hong, J.Y.,Hou, M.H. (deposition date: 2023-04-26, release date: 2024-02-07, Last modification date: 2024-03-06)

Primary citation

Hong, J.Y.,Lin, S.C.,Kehn-Hall, K.,Zhang, K.M.,Luo, S.Y.,Wu, H.Y.,Chang, S.Y.,Hou, M.H.
Targeting protein-protein interaction interfaces with antiviral N protein inhibitor in SARS-CoV-2.
Biophys.J., 123:478-488, 2024

PubMed Abstract: Coronaviruses not only pose significant global public health threats but also cause extensive damage to livestock-based industries. Previous studies have shown that 5-benzyloxygramine (P3) targets the Middle East respiratory syndrome coronavirus (MERS-CoV) nucleocapsid (N) protein N-terminal domain (N-NTD), inducing non-native protein-protein interactions (PPIs) that impair N protein function. Moreover, P3 exhibits broad-spectrum antiviral activity against CoVs. The sequence similarity of N proteins is relatively low among CoVs, further exhibiting notable variations in the hydrophobic residue responsible for non-native PPIs in the N-NTD. Therefore, to ascertain the mechanism by which P3 demonstrates broad-spectrum anti-CoV activity, we determined the crystal structure of the SARS-CoV-2 N-NTD:P3 complex. We found that P3 was positioned in the dimeric N-NTD via hydrophobic contacts. Compared with the interfaces in MERS-CoV N-NTD, P3 had a reversed orientation in SARS-CoV-2 N-NTD. The Phe residue in the MERS-CoV N-NTD:P3 complex stabilized both P3 moieties. However, in the SARS-CoV-2 N-NTD:P3 complex, the Ile residue formed only one interaction with the P3 benzene ring. Moreover, the pocket in the SARS-CoV-2 N-NTD:P3 complex was more hydrophobic, favoring the insertion of the P3 benzene ring into the complex. Nevertheless, hydrophobic interactions remained the primary stabilizing force in both complexes. These findings suggested that despite the differences in the sequence, P3 can accommodate a hydrophobic pocket in N-NTD to mediate a non-native PPI, enabling its effectiveness against various CoVs.

PubMed: 38234090
DOI: 10.1016/j.bpj.2024.01.013

Experimental method

X-RAY DIFFRACTION (2.7 Å)