6LNN

Crystal structure of MERS-CoV N-NTD complexed with ligand P4-1

Summary for 6LNN

• Entry DOI: 10.2210/pdb6lnn/pdb
• Descriptor: Nucleoprotein, 5-propoxy-1H-indole (3 entities in total)
• Functional Keywords: middle east respiratory syndrome coronavirus, nucleocapsid protein, n-terminal domain, viral protein
• Biological source: Middle East respiratory syndrome-related coronavirus
• Total number of polymer chains: 4
• Total formula weight: 57262.53

Authors

Hou, M.H.,Lin, S.M.,Hsu, J.N. (deposition date: 2019-12-31, release date: 2021-01-13, Last modification date: 2023-11-29)

Primary citation

Hsu, J.N.,Chen, J.S.,Lin, S.M.,Hong, J.Y.,Chen, Y.J.,Jeng, U.S.,Luo, S.Y.,Hou, M.H.
Targeting the N-Terminus Domain of the Coronavirus Nucleocapsid Protein Induces Abnormal Oligomerization via Allosteric Modulation.
Front Mol Biosci, 9:871499-871499, 2022

PubMed Abstract: Epidemics caused by coronaviruses (CoVs), namely the severe acute respiratory syndrome (SARS) (2003), Middle East respiratory syndrome (MERS) (2012), and coronavirus disease 2019 (COVID-19) (2019), have triggered a global public health emergency. Drug development against CoVs is inherently arduous. The nucleocapsid (N) protein forms an oligomer and facilitates binding with the viral RNA genome, which is critical in the life cycle of the virus. In the current study, we found a potential allosteric site (Site 1) using PARS, an online allosteric site predictor, in the CoV N-N-terminal RNA-binding domain (NTD) to modulate the N protein conformation. We identified 5-hydroxyindole as the lead via molecular docking to target Site 1. We designed and synthesized four 5-hydroxyindole derivatives, named P4-1 to P4-4, based on the pose of 5-hydroxyindole in the docking model complex. Small-angle X-ray scattering (SAXS) data indicate that two 5-hydroxyindole compounds with higher hydrophobic R-groups mediate the binding between N-NTD and N-C-terminal dimerization domain (CTD) and elicit high-order oligomerization of the whole N protein. Furthermore, the crystal structures suggested that these two compounds act on this novel cavity and create a flat surface with higher hydrophobicity, which may mediate the interaction between N-NTD and N-CTD. Taken together, we discovered an allosteric binding pocket targeting small molecules that induces abnormal aggregation of the CoV N protein. These novel concepts will facilitate protein-protein interaction (PPI)-based drug design against various CoVs.

PubMed: 35517857
DOI: 10.3389/fmolb.2022.871499

Experimental method

X-RAY DIFFRACTION (2.634 Å)