2. Academic Validation
  3. HKU25 clade MERS-related coronaviruses use ACE2 as a functional receptor

HKU25 clade MERS-related coronaviruses use ACE2 as a functional receptor

  • Nat Microbiol. 2025 Nov;10(11):2860-2874. doi: 10.1038/s41564-025-02152-y.
Chen Liu # 1,  Young-Jun Park # 2 3,  Cheng-Bao Ma 1,  Risako Gen 2,  Cameron Stewart 2,  Yu-Cheng Sun 1,  Xiao Yang 1,  Mei-Yi Lin 1,  Qing Xiong 1,  Jun-Yu Si 1,  Peng Liu 1,  David Veesler 4 5,  Huan Yan 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Virology and Biosafety, Hubei Provincial Research Center for Basic Biological Sciences, College of Life Sciences, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, China.
  • 2 Department of Biochemistry, University of Washington, Seattle, WA, USA.
  • 3 Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA.
  • 4 Department of Biochemistry, University of Washington, Seattle, WA, USA. [email protected].
  • 5 Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA. [email protected].
  • 6 State Key Laboratory of Virology and Biosafety, Hubei Provincial Research Center for Basic Biological Sciences, College of Life Sciences, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, China. [email protected].
  • # Contributed equally.
PMID: 41168429 DOI: 10.1038/s41564-025-02152-y
Abstract

Dipeptidyl peptidase-4 (DPP4) is an established receptor for Middle East respiratory syndrome-related coronaviruses (MERSr-CoVs), while recent studies have identified angiotensin-converting enzyme 2 (ACE2) usage in multiple merbecovirus clades. Yet, receptor usage of many genetically diverse bat MERSr-CoVs remains unclear. Here we show that broadly distributed HKU25 clade merbecoviruses use ACE2, rather than DPP4, as their receptor. Cryo-electron microscopy revealed that HsItaly2011 and VsCoV-a7 strains engage ACE2 similarly to HKU5 but with remodelled interfaces and distinct orthologue selectivity, suggesting a shared evolutionary origin of ACE2 recognition. EjCoV-3, a close relative of the DPP4-using BtCoV422, showed broad multi-species ACE2 tropism and preadaptation to human ACE2. Several ACE2 glycans and residues within or near the binding interface were identified as determinants of orthologue selectivity. These viruses remain sensitive to several broadly neutralizing antibodies and entry inhibitors, indicating potential countermeasures for future outbreaks. These findings highlight the versatility of ACE2 as a functional receptor for diverse coronaviruses.

Figures
Products