SARS-CoV-2 spike protein ectodomain (non-ACE2-binding site) (SARS-CoV-2 S protein)

The SARS-CoV-2 spike protein ectodomain outside the core ACE2-binding site encompasses critical structural regions including the N-terminal domain (NTD), the S2 subunit, and non-receptor-binding motif (non-RBM) epitopes within the receptor-binding domain (RBD) (UniProt P0DTC2). While the RBM is the primary site for viral attachment to the human ACE2 receptor, these peripheral regions are essential for the protein's stability, conformational transitions, and the eventual fusion of viral and host membranes (PubMed: 32155444). Therapeutic antibodies targeting these sites, such as Sotrovimab, often provide broader protection against emerging variants because these epitopes are typically more conserved than the rapidly mutating RBM (Nature: 583, 290–295). Drugs interacting with these regions function by sterically hindering receptor access, blocking the S1/S2 cleavage site, or preventing the S2 subunit from executing the "harpoon" mechanism required for cell entry (PubMed: 34254731). Consequently, this target area is a focal point for developing universal coronavirus vaccines and resilient monoclonal antibody cocktails.

Other names

Spike glycoproteinS proteinS1 subunit (non-RBM)S2 subunitN-terminal domain (NTD)SARS-CoV-2 S ectodomain

Neutralization of viral entry via steric hindrance of receptor binding, inhibition of S1/S2 subunit cleavage, or prevention of the S2-mediated membrane fusion process (PubMed: 32155444, 34254731).