Structural comparison of αCoV and βCoV spike (S) proteins. Top and side views of homotrimeric S proteins, which are colored in salmon, marine and pale green, of αCoV (HCoV-NL63, pdb: 5szs [204]) (a) and βCoV (MERS-CoV, pdb: 6q06 [148] and 5x59 [205]) (b). Notably, a difference in folding of the S1 subunit (white arrow) of each monomer of αCoV and βCoV S proteins results in a difference in positions of the S1-CTD subdomain, next to the S1-NTD subdomain in αCoV but substantially separated from S1-NTD in βCoV. Consequently, the αCoV S trimer has a simple intra-subdomain packing, whereas βCoV has an intricate cross-subdomain packing as shown in the top and side views. S1-NTD is located on the external surface of the S1 trimer. S1-NTD, which functions as a receptor binding site, typically recognizes a host sugar receptor, except for MHV S1-NTD, which recognizes CEACAM1. In contrast, S1-CTD is located on the internal surface of the S1 trimer in the lying state. S1-CTD can undergo dynamic conformational changes to the standing state for efficient binding to its receptor. After binding, S1-CTD will be stabilized in the standing conformation. So far, S1-CTD, which functions as a receptor binding site, has been found to bind to a host protein receptor.