Cell Rep. 2020 Oct 20; 33(3):108274.

PubMed ID: 33027617

An alternative binding mode of IGHV3-53 antibodies to the SARS-CoV-2 receptor binding domain

Wu NC, Yuan M, Liu H, Lee CD, Zhu X, Bangaru S, Torres JL, Caniels TG, Brouwer PJM, van Gils MJ, Sanders RW, Ward AB, Wilson IA

IGHV3-53-encoded neutralizing antibodies are commonly elicited during SARS-CoV-2 infection and target the receptor-binding domain (RBD) of the spike (S) protein. Such IGHV3-53 antibodies generally have a short CDR H3 because of structural constraints in binding the RBD (mode A). However, a small subset of IGHV3-53 antibodies to the RBD contain a longer CDR H3. Crystal structures of two IGHV3-53 neutralizing antibodies here demonstrate that a longer CDR H3 can be accommodated in a different binding mode (mode B). These two classes of IGHV3-53 antibodies both target the ACE2 receptor binding site, but with very different angles of approach and molecular interactions. Overall, these findings emphasize the versatility of IGHV3-53 in this common antibody response to SARS-CoV-2, where conserved IGHV3-53 germline-encoded features can be combined with very different CDR H3 lengths and light chains for SARS-CoV-2 RBD recognition and virus neutralization.