Structure of MERS-CoV spike receptor-binding domain complexed with human receptor DPP4

Abstract

The spike glycoprotein (S) of recently identified Middle East respiratory syndrome coronavirus (MERS-CoV) targets the cellular receptor, dipeptidyl peptidase 4 (DPP4). Sequence comparison and modeling analysis have revealed a putative receptor-binding domain (RBD) on the viral spike, which mediates this interaction. We report the 3.0 Å-resolution crystal structure of MERS-CoV RBD bound to the extracellular domain of human DPP4. Our results show that MERS-CoV RBD consists of a core and a receptor-binding subdomain. The receptor-binding subdomain interacts with DPP4 β-propeller but not its intrinsic hydrolase domain. MERS-CoV RBD and related SARS-CoV RBD share a high degree of structural similarity in their core subdomains, but are notably divergent in the receptor-binding subdomain. Mutagenesis studies have identified several key residues in the receptor-binding subdomain that are critical for viral binding to DPP4 and entry into the target cell. The atomic details at the interface between MERS-CoV RBD and DPP4 provide structural understanding of the virus and receptor interaction, which can guide development of therapeutics and vaccines against MERS-CoV infection.

Crystal Structure of the Receptor-Binding Domain from Newly Emerged Middle East Respiratory Syndrome Coronavirus

“…In addition, two other studies independently determined the crystal structure of MERS-CoV RBD (residues 367 to 606) complexed with human DPP4 (44,45). These studies delineated the molecular interactions between the MERS-CoV RBD and its receptor and confirmed that the accessory subdomain in the MERSCoV RBD is the DPP4-binding RBM.…”

A Comparative Review of Animal Models of Middle East Respiratory Syndrome Coronavirus Infection

“…Specifically, 14 amino acids in DPP4 appear to be critical in determining whether the MERS-CoV S can bind to DPP4. 70 MERS-CoV S cannot bind to DPP4 in species that have significant differences in these 14 amino acids as compared with human DPP4 (hDPP4), such as ferrets, hamsters, and mice; thus, these species are resistant to infection. 21,40,62,69 Species with few or no differences in the 14 amino acids seem to be susceptible to MERS-CoV, including rhesus macaques, common marmosets, and camels.…”

Mapping the Specific Amino Acid Residues That Make Hamster DPP4 Functional as a Receptor for Middle East Respiratory Syndrome Coronavirus

“…Therefore, if a treatment against MERS-CoV is shown to be successful in the mouse model, further characterization of the treatment needs to be performed in NHPs, a relatively expensive animal model to which access is limited. The availability of a second small-animal model (such as hamsters with a modified DPP4 [9,10]) to confirm results obtained with the mouse model would ensure that only treatments with a high likelihood of succeeding would be investigated in NHPs.Fourteen amino acids are important in the interaction between blades IV and V of human DPP4 (hDPP4) and the receptor binding domain (RBD) of the MERS-CoV spike protein (11,12). We previously showed that hamster DPP4 (haDPP4) does not function as a receptor for MERS-CoV.…”

“…Fourteen amino acids are important in the interaction between blades IV and V of human DPP4 (hDPP4) and the receptor binding domain (RBD) of the MERS-CoV spike protein (11,12). We previously showed that hamster DPP4 (haDPP4) does not function as a receptor for MERS-CoV.…”