SARS-CoV-2 spike protein ectodomain (non-RBD regions) (SARS-CoV-2 S (non-RBD))

The SARS-CoV-2 spike protein ectodomain outside the receptor-binding domain (RBD) includes the N-terminal domain (NTD) and the S2 fusion subunit (UniProt P0DTC2). While the RBD is the primary interface for ACE2 binding, the NTD facilitates initial attachment to host cells and is a major target for neutralizing antibodies like 4A8 (Chi et al., 2020, Science). The S2 subunit contains the fusion peptide and heptad repeats necessary for merging the viral envelope with the host cell membrane (Walls et al., 2020, Cell). Because the S2 subunit is more conserved across different coronavirus variants than the RBD, it is a strategic target for broadly neutralizing antibodies such as S2P6 (Pinto et al., 2021, Science). Therapeutic strategies targeting these non-RBD regions aim to prevent viral entry by inhibiting conformational changes or blocking auxiliary receptor interactions. This target is vital for developing treatments that remain effective against emerging variants that harbor mutations in the RBD (Harvey et al., 2021, Nature Reviews Microbiology). The structural complexity of these regions, particularly the S2 subunit's transition from pre-fusion to post-fusion states, provides multiple sites for pharmacological intervention (Huang et al., 2020, Nature Communications).

Other names

N-terminal domainNTDS2 subunitSpike protein S2Non-RBD spike regionsSpike protein ectodomain (non-RBD)

Neutralization of viral entry by blocking N-terminal domain-mediated attachment or inhibiting S2-mediated membrane fusion through stabilization of the pre-fusion conformation.