key: cord-0939822-yl8l30c7
authors: Wu, Nicholas C.; Yuan, Meng; Liu, Hejun; Lee, Chang-Chun D.; Zhu, Xueyong; Bangaru, Sandhya; Torres, Jonathan L.; Caniels, Tom G.; Brouwer, Philip J.M.; van Gils, Marit J.; Sanders, Rogier W.; Ward, Andrew B.; Wilson, Ian A.
title: An alternative binding mode of IGHV3-53 antibodies to the SARS-CoV-2 receptor binding domain
date: 2020-09-29
journal: Cell Rep
DOI: 10.1016/j.celrep.2020.108274
sha: 0e94b424b65291da8ff60365401c326c555521c9
doc_id: 939822
cord_uid: yl8l30c7

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 due to 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

). In contrast, binding mode 91 (mode B) of COVA2-39 is quite different and its Fab is rotated 180° along its long axis 92 relative to COVA2-04, thereby swapping the relative orientation of the light and heavy 

respectively, compared to 576 Å 2 and 128 Å 2 for COVA2-39. However, this BSA 105 difference does not translate into a corresponding difference in Fab binding affinity.

Specifically, the dissociation constants (K d ) for COVA2-04 and COVA2-39 to insect cell-107 expressed RBD are 40 nM and 21 nM, respectively ( Figure 1D ). COVA2-04 exhibits 108 slow-on/slow-off kinetics, whereas COVA2-39 has fast-on/fast-off kinetics. Despite the 6 16 are within the epitope of COVA2-04 and 11 within the epitope of COVA2-39 ( Figure   117 2A-C). The difference in angles of approach and apparent avidity of the IgG interaction 118 in the context of the spike trimer appear to allow COVA2-39 attain higher neutralization 119 potency, similar to avidity effects for IgG of some antibodies to influenza hemagglutinin to the RBD in more configurations of the RBD on the spike than COVA2-04 and increase residues on the RBD. V H Y33 of the 32 NY 33 motif is retained and forms a π−π stacking 143 interaction between its aromatic ring with the aromatic side chain of Y489 ( Figure 3C ).

Although V H N32 in COVA2-39 does not interact with the RBD, both its side chain and 145 main chain participate in a 3 10 turn to stabilize the CDR H1 backbone ( Figure 3C 158 RBD by at least 50-fold ( Figure 1D and Figure S4A ). The increased binding for 53 TGGT 56 159 is likely due to the methyl groups in V H T53 and T56, which make additional van der 160 Waals interactions ( Figure S4B ). 

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Substantial undocumented infection facilitates the rapid dissemination of novel 499 coronavirus (SARS-CoV-2)

Phaser crystallographic software

Processing of X-ray diffraction data collected in 503 oscillation mode

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Isolation of potent SARS-CoV-2 neutralizing 509 antibodies and protection from disease in a small animal model

Repertoire Builder: high-throughput structural modeling of B and 512 T cell receptors

Analysis of a SARS-CoV-2-515 infected individual reveals development of potent neutralizing antibodies with limited 516 somatic mutation

The electrostatic potential of the alpha helix 518 (electrostatic potential/α-helix/secondary structure/helix dipole)

A human neutralizing antibody targets the receptor binding site of SARS