Dipeptidase 1 is a functional receptor for coronavirus PHEV

Coronaviruses of the subgenus Embecovirus include several relevant pathogens such as the human seasonal coronaviruses HKU1 and OC43, bovine coronavirus, and porcine hemagglutinating encephalomyelitis virus (PHEV), among others. While sialic acid is thought to be required for embecovirus entry, protein receptors are unknown in most cases. Here we show that PHEV does not require sialic acid for entry and uses dipeptidase 1 (DPEP1) as a receptor. Cryo-electron microscopy revealed that PHEV, unlike other embecoviruses, samples open and closed conformations of its spike trimer at steady state. We found that the receptor binding domain (RBD) of the PHEV spike shares no detectable sequence homology or receptor usage with those of closely related viruses. In contrast, the X-ray structure of the RBD/DPEP1 complex showed that the elements involved in receptor binding are conserved across embecoviruses, revealing a striking versatility of the RBD to accommodate highly variable sequences that confer novel receptor specificities.