Structural basis of a shared antibody response to SARS-CoV-2

Abstract

Molecular understanding of neutralizing antibody responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could accelerate vaccine design and drug discovery. We analyzed 294 anti-SARS-CoV-2 antibodies and found that immunoglobulin G heavy-chain variable region 3-53 (IGHV3-53) is the most frequently used IGHV gene for targeting the receptor-binding domain (RBD) of the spike protein. Co-crystal structures of two IGHV3-53-neutralizing antibodies with RBD, with or without Fab CR3022, at 2.33- to 3.20-angstrom resolution revealed that the germline-encoded residues dominate recognition of the angiotensin I converting enzyme 2 (ACE2)-binding site. This binding mode limits the IGHV3-53 antibodies to short complementarity-determining region H3 loops but accommodates light-chain diversity. These IGHV3-53 antibodies show minimal affinity maturation and high potency, which is promising for vaccine design. Knowledge of these structural motifs and binding mode should facilitate the design of antigens that elicit this type of neutralizing response.

Fig. 1. Structures of two IGHV3-53 antibodies.

(A) The distribution of IGHV gene usage is shown for a total of 294 RBD-targeting antibodies (–28). (B to D) Crystal structures of (B) CC12.1 in complex with SARS-CoV-2 RBD, (C) CC12.3 with SARS-CoV-2 RBD, and (D) human ACE2 with SARS-CoV-2 RBD (PDB 6M0J) (12).

Fig. 2. Epitopes of IGHV3-53 antibodies.

(A to C) Epitopes of (A) CC12.1, (B) CC12.3, and (C) B38 (PDB 7BZ5) (23). Epitope residues contacting the heavy chain are shown in orange and those contacting the light chain are shown in yellow. CDR loops are labeled in the left panels; epitope residues are labeled in the right panels. For clarity, only representative epitope residues are labeled. Epitope residues that are also involved in ACE2 binding are shown in red. (D) ACE2-binding residues are shown in blue. ACE2 is shown in green in the left panel in a semitransparent cartoon representation. ACE2-binding residues are labeled in the right panel. A total of 17 residues were used for ACE2 binding (12), but only 15 are labeled here because the other two are at the back of the structure in this view and do not interact with the antibodies here. (E) Epitope residues for CC12.1, CC12.3, and B38 were identified by PISA (41) and annotated on the SARS-CoV-2 RBD sequence, which is aligned to the SARS-CoV RBD sequence with nonconserved residues highlighted. The 17 ACE2-binding residues were identified from a SARS-CoV-2 RBD–ACE2 complex structure as described previously (12).

Fig. 3. Interactions between the RBD and heavy-chain CDR loops.

(A to C) Highly similar interaction modes between SARS-CoV-2 RBD and the antibody CDR H1 and H2 loops, but not the H3 loop, are observed for (A) CC12.1, (B) CC12.3, and (C) B38 (PDB 7BZ5) (23). The RBD is shown in white and antibody residues in cyan, pink, and dark gray, respectively. Oxygen atoms are shown in red and nitrogen atoms in blue. Hydrogen bonds are represented by dashed lines. (D) Interaction between ACE2 (green) and residues of the RBD (PDB 6M0J) (12) shown in (A) to (C).

Fig. 4. Two IGHV3-53 germline-encoded motifs with a short CDR H3.

(A) Illustration of the extensive hydrogen bond network that involves V_H N32 of the NY motif in CDR H1. (B) Hydrophobic cage interaction between the RBD and V_H Y33 of the NY motif in CDR H1. (C) Hydrogen bond network that involves the SGGS motif in CDR H2. CC12.3 is shown here because its structure is at higher resolution than CC12.1. (D) CDR H3 length is constrained to fit in a relatively small pocket on the RBD surface. The heavy and light chains of CC12.1 (cyan) and the RBD (white) are shown in surface representation, with CDR H3 (red) highlighted in the diagram in the left panel. CC12.3 (pink) is shown in the right panel in the same representation.