A hybrid structure determination approach to investigate the druggability of the nucleocapsid protein of SARS-CoV-2

The ongoing pandemic caused by SARS-CoV-2 has called for concerted efforts
to generate new insights into the biology of betacoronaviruses to inform
drug screening and development. Here, we establish a workflow to determine
the RNA recognition and druggability of the nucleocapsid N-protein of
SARS-CoV-2, a highly abundant protein crucial for the viral life cycle. We
use a synergistic method that combines NMR spectroscopy and protein-RNA
cross-linking coupled to mass spectrometry to quickly determine the RNA
binding of two RNA recognition domains of the N-protein. Finally, we
explore the druggability of these domains by performing an NMR fragment
screening. This workflow identified small molecule chemotypes that bind to
RNA binding interfaces and that have promising properties for further drug
development. This deposition contains the NMR data acquired to determine
the structural features of RBDs- RNA recognition as well as selected
relevant data regarding the characterization of promising molecular
fragments to disrupt protein-RNA interaction. Furthermore, we included the
molecular docking files used to obtain the reported structural model.