Severe acute respiratory syndrome coronavirus 2 spike protein (non-RBD regions) (SARS-CoV-2 S protein (non-RBD))

The SARS-CoV-2 spike (S) protein is a class I fusion glycoprotein responsible for viral attachment and entry into host cells (UniProt P0DTC2). While the receptor-binding domain (RBD) is the most prominent target for drug development, the regions outside the RBD, specifically the N-terminal domain (NTD) of the S1 subunit and the entire S2 subunit, are vital for the infection process. The NTD is thought to facilitate initial viral attachment to the cell surface and may interact with alternative receptors or co-receptors (McCallum et al., 2021). The S2 subunit contains the fusion machinery, including the fusion peptide and heptad repeat regions, which undergo a dramatic conformational change to merge the viral and host membranes (Xia et al., 2019). Therapeutic interventions targeting these regions include neutralizing antibodies that bind the NTD supersite and fusion inhibitors that block the S2 conformational transition (Chi et al., 2020). Because these regions, particularly S2, are more conserved across coronavirus variants than the RBD, they represent important targets for universal vaccine and broad-spectrum therapeutic development. Understanding the structural dynamics of these non-RBD regions is essential for overcoming viral escape mutations seen in the RBD.

Other names

SARS-CoV-2 S1 N-terminal domainSARS-CoV-2 S2 subunitSpike protein non-RBD regionsSARS-CoV-2 S1/S2SARS-CoV-2 S protein NTD

Neutralization of viral entry by blocking N-terminal domain-mediated attachment or inhibiting S2-mediated membrane fusion between the viral envelope and host cell membrane (Chi et al., 2020; Xia et al., 2019).