MERS-CoV infection is initiated by attachment of its homotrimeric S proteins to a host cell. By mass spectrometric analysis, dipeptidyl peptidase 4 (DPP4 or CD26) was identified to be a ∼110-kDa protein co-purified with MERS-CoV S1–Fc chimeric protein from the human liver (Huh-7) and African green monkey kidney (Vero) lysates. Pre-incubation of Huh-7 cells and primary human bronchial epithelial cells with anti-DPP4 immunoglobulin appeared to inhibit MERS-CoV infection. Based on these findings, MERS-CoV infection was suggested to occur via binding of MERS-CoV S1 to the cellular receptor DDP4 [249]. According to the site of virus infection in individual hosts, DDP4 was detected in the respiratory tracts of camelids and humans and was found to be rich in the intestinal tracts of pipistrelle bats, the hosts of Pipistrellus bat CoV HKU5 (Pi-BatCoV HKU5), which is closely related to MERS-CoV [108,131]. Like other protein-binding CoVs, except for MHV binding to the protein receptor CEACAM1 via S1-NTD [250] (Table 2), MERS-CoV binds to the outer surface of DDP4 via S1B (S1-CTD) and it does not bind to the DDP4 catalytic pocket and does not require DDP4 catalytic activity (Figure 4b) [251]. In a cryo-EM study, each monomeric S1-CTD receptor binding surface was found to be buried in the tip of the CoV S trimer in the lying state (closed conformation, pdb: 6q06) and to be exposed in the standing state (open conformation, pdb: 5 × 59) (Figure 6b) readily bound by the receptor (Figure 9, left) [205]. Analysis of the crystal structure of MERS-CoV S1-CTD in complex with DDP4 (pdb: 4l72) revealed the location of the DDP4 binding site on MERS-CoV S1-CTD (Figure 9, left) and the viral S1-CTD binding site on DDP4 (Figure 4b) and provided information on interactions between the viral S1-CTD and DDP4 [251]. Eight H-bond formations were observed between residues on the viral S1-CTD and residues on the DPP4 as follows: (i) Y499 with R336, (ii) D510 with R317, (iii) D510 with Y322, (iv) E513 with Q344, (v) E513 with A291, (vi) G538 with Q286, (vii) D539 with K267, and (viii) R542 with L294 (Figure 9, middle).