Structures and receptor binding activities of merbecovirus spike proteins reveal key signatures for human DPP4 adaptation

Sci Adv. 2025 Jul 11;11(28):eadv7296. doi: 10.1126/sciadv.adv7296. Epub 2025 Jul 11.

Abstract

Merbecoviruses from bats, pangolins, and hedgehogs pose significant zoonotic threats, with a limited understanding of receptor binding by their spike (S) proteins. Here, we report cryo-EM structures of GD-BatCoV (BtCoV-422) and SE-PangolinCoV (MjHKU4r-CoV-1) RBDs in complex with human DPP4 (hDPP4). These structures exhibit a substantial offset in their hDPP4 interaction interfaces, revealing a conserved hydrophobic cluster as a convergent signature of DPP4 binding within the MERS-HKU4 clade of merbecoviruses. Structure-guided mutagenesis demonstrates that favorable interactions are distributed across multiple receptor binding motif (RBM) regions, working synergistically to confer high-affinity hDPP4 binding. Swapping of the merbecovirus RBM regions indicate limited plasticity and interchangeability among these regions. In addition, we report cryo-EM structures of six merbecovirus S-trimers. Structure-based phylogenetics suggests that hDPP4-binding merbecoviruses undergo convergent evolution, while ACE2-binding merbecoviruses exhibit diversification in their binding mechanisms. These findings offer critical insights into merbecovirus receptor utilization, providing a structural understanding for future surveillance.

MeSH terms

  • Animals
  • Binding Sites
  • Cryoelectron Microscopy
  • Dipeptidyl Peptidase 4* / chemistry
  • Dipeptidyl Peptidase 4* / metabolism
  • Humans
  • Models, Molecular
  • Protein Binding
  • Spike Glycoprotein, Coronavirus* / chemistry
  • Spike Glycoprotein, Coronavirus* / genetics
  • Spike Glycoprotein, Coronavirus* / metabolism

Substances

  • Spike Glycoprotein, Coronavirus
  • Dipeptidyl Peptidase 4
  • DPP4 protein, human