Molecular basis of convergent evolution of ACE2 receptor utilization among HKU5 coronaviruses
DPP4 was considered a canonical receptor for merbecoviruses until the recent discovery of African bat-borne MERS-related coronaviruses using ACE2. The extent and diversity of ACE2 utilization among merbecoviruses and their receptor species tropism remain unknown. Here, we reveal that HKU5 enters host cells utilizing Pipistrellus abramus (P.abr) and several non-bat mammalian ACE2s through a binding mode distinct from that of any other known ACE2-using coronaviruses. We defined the molecular determinants of receptor species tropism and identified a single amino acid mutation enabling HKU5 to utilize human ACE2, providing proof of principle for machine-learning-assisted outbreak preparedness. We show that MERS-CoV and HKU5 have markedly distinct antigenicity and identified several HKU5 inhibitors, including two clinical compounds. Our findings profoundly alter our understanding of coronavirus evolution, as several merbecovirus clades independently evolved ACE2 utilization, and pave the way for developing countermeasures against viruses poised for human emergence.
Authors
- M. Alejandra Tortorici (ORCID: https://orcid.org/0000-0002-2260-2577)
- Jack T Brown (ORCID: https://orcid.org/0000-0002-6159-2148)
- Huan Yan (ORCID: https://orcid.org/0000-0001-8744-8665)
- Tyler N. Starr (ORCID: https://orcid.org/0000-0001-6713-6904)
- Amin Addetia (ORCID: https://orcid.org/0000-0001-6703-3841)
- Cameron Stewart (ORCID: https://orcid.org/0000-0002-2786-6256)
- Abeer N. Alshukairi (ORCID: https://orcid.org/0000-0002-9565-3527)
- Risako Gen (ORCID: https://orcid.org/0009-0004-4416-0417)
- Caroline J. Craig (ORCID: https://orcid.org/0000-0002-9528-563X)
- Young‐Jun Park (ORCID: https://orcid.org/0000-0003-2901-6949)
- Chengbao Ma
- Jimin Lee (ORCID: https://orcid.org/0000-0001-5849-7732)
- David Veesler (ORCID: https://orcid.org/0000-0002-6019-8675)
- Chen Liu (ORCID: https://orcid.org/0009-0003-0430-6146)
- Peng Liu (ORCID: https://orcid.org/0000-0002-5164-088X)
- Qing Xiong (ORCID: https://orcid.org/0000-0002-8656-2041)
- Samantha K. Zepeda
Institutions
- Alfaisal University (SA)
- Howard Hughes Medical Institute (US)
- University of Washington (US)
- University of Utah (US)
- University of Washington Medical Center (US)
- Wuhan University (CN)
- Wuhan Institute of Virology (CN)
Publication Details
- Journal
- Cell
- Published
- 2025-02-07
- DOI
- https://doi.org/10.1016/j.cell.2024.12.032
- Citations
- 40
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 55.85
Funders
- Howard Hughes Medical Institute
- University of Washington
- National Natural Science Foundation of China
- Fudan University
- Natural Science Foundation of Hubei Province
- Tsinghua University
- National Institutes of Health
- Fundamental Research Funds for the Central Universities
- National Institute of General Medical Sciences
- National Institute of Allergy and Infectious Diseases