Unknown

Dataset Information

0

Structure-Based Stabilization of Non-native Protein-Protein Interactions of Coronavirus Nucleocapsid Proteins in Antiviral Drug Design.


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.

SUBMITTER: Lin SM 

PROVIDER: S-EPMC7094172 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

altmetric image

Publications

Structure-Based Stabilization of Non-native Protein-Protein Interactions of Coronavirus Nucleocapsid Proteins in Antiviral Drug Design.

Lin Shan-Meng SM   Lin Shih-Chao SC   Hsu Jia-Ning JN   Chang Chung-Ke CK   Chien Ching-Ming CM   Wang Yong-Sheng YS   Wu Hung-Yi HY   Jeng U-Ser US   Kehn-Hall Kylene K   Hou Ming-Hon MH  

Journal of medicinal chemistry 20200311 6


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  ...[more]

Similar Datasets

| S-EPMC8546642 | biostudies-literature
| S-EPMC4836358 | biostudies-literature
| S-EPMC289081 | biostudies-other
| S-EPMC2894783 | biostudies-literature
| S-EPMC7658559 | biostudies-literature
| S-EPMC9605790 | biostudies-literature
| S-EPMC2258912 | biostudies-literature
| S-EPMC4844985 | biostudies-literature
| S-EPMC7103675 | biostudies-literature
| S-EPMC5515880 | biostudies-literature