%0 Journal Article %A Clara G. Altomare %A Daniel C. Adelsberg %A Juan Manuel Carreno %A Iden A. Sapse %A Fatima Amanat %A Ali H. Ellebedy %A Viviana Simon %A Florian Krammer %A Goran Bajic %T Structure of a germline-like human antibody defines a neutralizing epitope on the SARS-CoV-2 spike NTD %D 2021 %R 10.1101/2021.07.08.451649 %J bioRxiv %P 2021.07.08.451649 %X Structural characterization of infection- and vaccination-elicited antibodies in complex with antigen provides insight into the evolutionary arms race between the host and the pathogen and informs rational vaccine immunogen design. We isolated a germline-like monoclonal antibody (mAb) from plasmablasts activated upon mRNA vaccination against SARS-CoV-2 and determined its structure in complex with the spike glycoprotein by cryo-EM. We show that the mAb engages a previously uncharacterized neutralizing epitope on the spike N-terminal domain (NTD). The high-resolution structure reveals details of the intermolecular interactions and shows that the mAb inserts its HCDR3 loop into a hydrophobic NTD cavity previously shown to bind a heme metabolite, biliverdin. We demonstrate direct competition with biliverdin and that - because of the conserved nature of the epitope – the mAb maintains binding to viral variants B.1.1.7 and B.1.351. Our study illustrates the feasibility of targeting the NTD to achieve broad neutralization against SARS-CoV-2 variants.Competing Interest StatementThe authors have declared no competing interest. %U https://www.biorxiv.org/content/biorxiv/early/2021/07/08/2021.07.08.451649.full.pdf