To enter cells, 229E viruses must bind to aminopeptidase N (APN) receptors (Figure 7a), dimeric glycoproteins that protrude from the epithelial cell surface (Figure 4b). Analysis of the crystal structures of HCoV-229E from four of six different classes that replaced each other in the human population [83], classified by an RBD sequence variant (aa 302–417), in complex with human APN (hAPN) revealed locations of a viral binding site (VBS) on hAPN (Figure 4b) and a receptor binding site (RBS) on the viral RBD (Figure 7b). The RBS is composed of residues with red letter codes (Figure 7c) in loops 1, 2 and 3 (residues 308–408 based on class I numbering, Figure 7b) on a six-stranded β-sheet peptide (Figure 7a). It should be noted that these loops are immunogenic [206]. The virus diverged into different classes with highly variable residues in the exposed loop sequences in order to evade neutralization by antibodies as observed by using IgG1 monoclonal antibodies against class I, a reference strain, in a viral infection inhibition assay [83]. Results of surface plasmon resonance binding assays showed that these virus variants had differences in binding affinity for hAPN receptors [83]. These differences in binding affinity might be for optimal escape and entry due to adaptation and selection of the virus to continue circulation under the condition of host environment pressure.