Insights into SARS-CoV-2 nucleocapsid protein and its interaction with polyanions

The SARS-CoV-2 nucleocapsid (N) protein plays key roles in RNA packaging and replication, combining structured domains (NTD, CTD) with extensive intrinsically disordered regions (IDRs). This study compares the binding of three protein constructs—NTD, NTR, and full-length (FL)—to heparin-based ligands of varying length. NMR results reveal that longer ligands bind more strongly, and that IDRs significantly enhance binding affinity and modulate interaction profiles. The FL protein shows distinct behavior, likely due to additional binding via IDR3 and dimerization. These findings highlight the active role of IDRs in ligand recognition and the importance of studying full-length proteins.