1991. SD1 for the spikes function, and we discuss the potential availability of a novel common epitope among the SARS-CoV-2 variants. IMPORTANCE Novel severe acute respiratory syndrome coronavirus 2 variants with immune evasion ability are still repeatedly emerging, nonetheless, a part of immunity developed in responding to the antigen of earlier variants retains efficacy against recent variants irrespective of the numerous mutations. In exploration for the broadly effective antibodies, we identified a cross-neutralizing antibody, named MO11, from the B cells of the convalescent patient. MO11 targets a novel epitope in subdomain 1 (SD1) and was effective against all emerging variants including XBB.1.16 and EG.5.1. The neutralizing activity covering from D614G to EG.5.1 variants was explained by the conservation of the epitope, and it revealed the importance of the subdomain on regulating the function of the antigen for viral infection. Demonstrated identification of the neutralizing antibody that recognizes a conserved epitope implies basal contribution of such group of antibodies for prophylaxis against COVID-19. KEYWORDS: severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), Omicron variants, human monoclonal antibody, broadly neutralizing activity, spike, subdomain 1, cryoelectron microscopy, common epitope, vaccine INTRODUCTION The spike antigen of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is usually a key molecule in the control of coronavirus disease 2019 (COVID-19). The continuous evolution of SARS-CoV-2 since the emergence of the virus at the end of 2019 has been driven by increasing mutations in the spike via interactions with host immunity, especially with neutralizing antibodies elicited by TAME contamination and/or vaccination. In the 1,273 amino acid residues of the spike, mutations are concentrated mostly in the receptor-binding domain name (RBD), which binds to the host-receptor angiotensin-converting enzyme 2 (ACE2) (1), and numerous mutations have also been identified in the N-terminal domain name (NTD) of the virus (Fig. 1A and B), especially after the emergence of the Omicron variant at the end of 2021. The biased mutation frequency indicated that neutralizing antibodies targeting these domains are imposing selection pressure in human bodies, but SARS-CoV-2 has escaped this pressure by undergoing ingenious modifications in the epitopes without losing their function. Open in a separate window Fig 1 Domain name structure of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike antigen and reported mutations. (A) Structural domains of the spike antigen considering each fold in the 3D structure and mutation sites in major SARS-CoV-2 variants. NTD, N-terminal domain name; SD1, subdomain 1; SD2, subdomain 2; RBD, receptor binding domain name. Mutation positions are shown TAME for the selected major variants. The S1/S2 and the S2 cleavage sites are also indicated. (B) A schematic illustration of Rabbit Polyclonal to MAST4 a spike protomer, showing the spatial arrangement of the domains. SD1 and SD2 were composed of two distant parts, unlike the other domains. The SARS-CoV-2 spike protein forms a trimer and serves as a molecular machinery that TAME undergoes dynamic structural changes during infection around the SARS-CoV-2 virion. The spike has a furin cleavage site at RRAR682-685 and is divided into S1 and S2 domains during virion assembly and maturation while tethered by a single-pass transmembrane domain name at the C-terminal region (Fig. 1A and B). The S1 domain name contains the NTD and an RBD as well as small domains called subdomain (SD)1 and SD2, and the S2 domain name forms a helical core of the trimer. The NTD and RBD each consist of a continuous region and form a single fold uncovered at the tip of the spike, and SD1 and SD2 are separated in the primary structure (Fig. 1A and B). The pre-fusion spike trimer is not static, as the.