Cell biology

Biology

Virology

Receptor

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)

Computational biology

Coronavirus disease 2019 (COVID-19)

Genetics

Mathematics

Binding site

Domain (mathematical analysis)

Infectious disease (medical specialty)

Internal medicine

Mathematical analysis

Medicine

Chemistry

Disease

Immunoglobulin light chain

Antibody

Cell Reports

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.

An Alternative Binding Mode of IGHV3-53 Antibodies to the SARS-CoV-2 Receptor Binding Domain