Molecular basis for receptor recognition and broad host tropism for merbecovirus MjHKU4r-CoV-1

EMBO Rep. 2024 Jul;25(7):3116-3136. doi: 10.1038/s44319-024-00169-8. Epub 2024 Jun 14.

Abstract

A novel pangolin-origin MERS-like coronavirus (CoV), MjHKU4r-CoV-1, was recently identified. It is closely related to bat HKU4-CoV, and is infectious in human organs and transgenic mice. MjHKU4r-CoV-1 uses the dipeptidyl peptidase 4 (DPP4 or CD26) receptor for virus entry and has a broad host tropism. However, the molecular mechanism of its receptor binding and determinants of host range are not yet clear. Herein, we determine the structure of the MjHKU4r-CoV-1 spike (S) protein receptor-binding domain (RBD) complexed with human CD26 (hCD26) to reveal the basis for its receptor binding. Measuring binding capacity toward multiple animal receptors for MjHKU4r-CoV-1, mutagenesis analyses, and homology modeling highlight that residue sites 291, 292, 294, 295, 336, and 344 of CD26 are the crucial host range determinants for MjHKU4r-CoV-1. These results broaden our understanding of this potentially high-risk virus and will help us prepare for possible outbreaks in the future.

Keywords: CD26; Interspecies Transmission; MjHKU4r-CoV-1; RBD; Virus Entry.

MeSH terms

  • Animals
  • Binding Sites
  • Dipeptidyl Peptidase 4* / genetics
  • Dipeptidyl Peptidase 4* / metabolism
  • Host Specificity*
  • Host Tropism
  • Humans
  • Mice
  • Models, Molecular
  • Protein Binding*
  • Protein Domains
  • Receptors, Virus* / chemistry
  • Receptors, Virus* / genetics
  • Receptors, Virus* / metabolism
  • Spike Glycoprotein, Coronavirus* / chemistry
  • Spike Glycoprotein, Coronavirus* / genetics
  • Spike Glycoprotein, Coronavirus* / metabolism
  • Viral Tropism*
  • Virus Internalization

Substances

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