SARS-CoV-2 spike protein receptor-binding domain (RBD) conserved cryptic outer-surface epitope (RBD cryptic outer-surface epitope)

The conserved cryptic outer-surface epitope of the SARS-CoV-2 spike protein receptor-binding domain (RBD) is a highly stable antigenic site located on the outer face of the RBD core, distinct from the rapidly mutating receptor-binding motif (RBM). This epitope, often referred to as Site V or the S2H97 site, is considered cryptic because it is typically shielded within the spike trimer and only becomes accessible when the RBDs adopt an up conformation or through stochastic breathing of the protein. Because this region is highly conserved across the sarbecovirus subgenus, including SARS-CoV and various bat coronaviruses, it is a primary target for the development of broadly neutralizing antibodies and universal vaccines. Antibodies targeting this site, such as S2H97, can neutralize a wide range of variants by either sterically hindering ACE2 receptor engagement or by triggering the premature dissociation of the S1 subunit from the spike trimer. This target is particularly valuable for therapeutic strategies aimed at overcoming the immune evasion seen in highly mutated variants like Omicron.

Other names

Site VS2H97 epitopePan-sarbecovirus cryptic epitopeRBD-8 epitopeConserved sarbecovirus cryptic epitope

Neutralization of viral entry by blocking ACE2 receptor binding or inducing structural instability and shedding of the S1 subunit from the spike trimer.