6KL6

Crystal structure of MERS-CoV N-NTD complexed with 5-Benzyloxygramine

Summary for 6KL6

• Entry DOI: 10.2210/pdb6kl6/pdb
• Descriptor: Nucleoprotein, N,N-dimethyl-1-(5-phenylmethoxy-1H-indol-3-yl)methanamine (3 entities in total)
• Functional Keywords: middle east respiratory syndrome coronavirus, nucleocapsid protein, n-terminal domain, 5-benzyloxygramine, viral protein
• Biological source: Middle East respiratory syndrome-related coronavirus
• Total number of polymer chains: 4
• Total formula weight: 63702.63

Authors

Hou, M.H.,Lin, S.M.,Wang, Y.S.,Hsu, J.N. (deposition date: 2019-07-29, release date: 2020-03-25, Last modification date: 2023-11-22)

Primary citation

Lin, S.M.,Lin, S.C.,Hsu, J.N.,Chang, C.K.,Chien, C.M.,Wang, Y.S.,Wu, H.Y.,Jeng, U.S.,Kehn-Hall, K.,Hou, M.H.
Structure-Based Stabilization of Non-native Protein-Protein Interactions of Coronavirus Nucleocapsid Proteins in Antiviral Drug Design.
J.Med.Chem., 63:3131-3141, 2020

PubMed Abstract: Structure-based stabilization of protein-protein interactions (PPIs) is a promising strategy for drug discovery. However, this approach has mainly focused on the stabilization of native PPIs, and non-native PPIs have received little consideration. Here, we identified a non-native interaction interface on the three-dimensional dimeric structure of the N-terminal domain of the MERS-CoV nucleocapsid protein (MERS-CoV N-NTD). The interface formed a conserved hydrophobic cavity suitable for targeted drug screening. By considering the hydrophobic complementarity during the virtual screening step, we identified 5-benzyloxygramine as a new N protein PPI orthosteric stabilizer that exhibits both antiviral and N-NTD protein-stabilizing activities. X-ray crystallography and small-angle X-ray scattering showed that 5-benzyloxygramine stabilizes the N-NTD dimers through simultaneous hydrophobic interactions with both partners, resulting in abnormal N protein oligomerization that was further confirmed in the cell. This unique approach based on the identification and stabilization of non-native PPIs of N protein could be applied toward drug discovery against CoV diseases.

PubMed: 32105468
DOI: 10.1021/acs.jmedchem.9b01913

Experimental method

X-RAY DIFFRACTION (2.77 Å)