Fig. 9.

A The sequence of SARS-CoV-2 RBD from residue 317 to residue 532, annotated with sequence of the RBM (thick underline) and the 17 residues to which human ACE2 bind (blue shaded). Additionally, mutations found in each of the major variants (yellow shaded residues; gray shaded for those mutations only found in some of the isolates of that variant), and epitopes for ten single-domain nanobodies known to target SARS-CoV-2 RBD (shaded green) are provided. The epitopes were retrieved from several references, including Wrapp et al. [238], Koenig et al. [249], Margulies et al. [345], Sun et al. [342], Gűttler et al. [343], Schoof et al. [346], and Hanke et al. [344]. Additional epitopes not adequately described in the literature were determined or corrected using the Protein Data Bank entries for the RBD-antibody co-crystal structures, with identification of the epitopes based on residues within 5Å of antibody loops. B Structures of SARS-CoV-2 RBD, the ACE2 binding site, and the epitopes for anti-RBD nanobodies from co-crystal structures. The PDB ID entry used to generate top is given below for each [202]; and (ii) a filled structure of RBD (PDB ID 7CH5 [351]) showing the ACE2 binding site (white; refer to Fig. 4 for baseline information) and the epitope on RBD to which the antibody binds (green). B1. RBD showing ACE2 binding site (white); B2. Epitope for Nb6, overlapping ACE2 binding site (PDB ID 7KKK [255]); B3. Epitope for Sb14, overlapping ACE2 binding site (PDB ID 7MFU [240]); B4. Epitope for Re5D06, overlapping ACE2 binding site (PDB ID 7OLZ [253]); B5. Epitope for VHH-E, overlapping ACE2 binding site (PDB ID 7KSG [115]); B6. Epitope for Nb21 (precursor to PiN21), overlapping ACE2 binding site (PDB ID 7N9B [252]); B7. Epitope for VHH-72, which does not overlap ACE2 binding site (PDB ID 6WAQ [105]); B8. Epitope for VHH-V, which does not overlap ACE2 binding site (PDB ID 7B11 [249]). Note that VHH antibodies Nb6, Sb14, Re5D06, VHH-E, and Nb21 fall into our RBD-2 epitope class (see Figs. 6 and 7) and VHH-72 and VHH-V fall into our RBD-6 epitope class. Nanobody Fu2 [344] binds to both the RBD-2 and the RBD-6 epitopes. The PDB program [201, 202] was used to generate and annotate the structures. ACE2 angiotensin-converting enzyme-2, PDB ID Protein Data Bank Identifier, RBD receptor binding domain, RBM receptor binding motif, SARS-CoV-2 severe acute respiratory syndrome coronavirus-2, VHH single domain antibody