NTD loops on the SARS-CoV-2 spike protein. (a, left) SARS-CoV-2 S cryo-EM structure (PDB accession no. 6VSB) in surface representation. The N-terminal domain (NTD; orange) and receptor-binding domain (RBD; green) are depicted in the context of the trimer ectodomain (gray). Unresolved NTD loops are depicted by dotted lines (red, blue, and purple). Resolved residues nearest to the NTD loops are in cyan. (Right) A single S monomer is depicted in a ribbon diagram with RBD-up (dark green) superimposed on RBD-down (light green). D614 is labeled in red. (b) Linear depiction of the complete SARS-CoV-2 S protein. The NTD (orange), the RBD (green), C-terminal domain 1 (CTD1), C-terminal domain 2 (CTD2), D614, S1/S2 priming, the S2′-activating cleavage sites, the fusion peptide (FP), the fusion peptide-proximal region (FPPR), heptad repeat 1 (HR1), the central helix (CH), the connector domain (CD), heptad repeat 2 (HR2), the transmembrane span (TM), and the cytoplasmic tail (CT) are depicted. Three NTD loops are highlighted in colored boxes (red, blue, and purple) and enlarged to reveal the amino acid sequences of SARS-CoV-2-S (GenBank accession no. NC_045512.2) and corresponding SARS-CoV-S (GenBank accession no. AY278741.1), which were exchanged. (c) Recombinant spike protein pairs. (Top) SARS-1 in comparison with SARS1/2 (SARS-2 NTD loops in color); (middle) SARS-2 in comparison with SARS-2/1 (SARS-1 NTD loops not in color); (bottom) SARS-2 and SARS-2/1 in the D614G background.