Multiple independent acquisitions of ACE2 usage in MERS-related coronaviruses
The angiotensin-converting enzyme 2 (ACE2) receptor is shared by various coronaviruses with distinct receptor-binding domain (RBD) architectures, yet our understanding of these convergent acquisition events remains elusive. Here, we report that two bat MERS-related coronaviruses (MERSr-CoVs) infecting Pipistrellus nathusii (P.nat)-MOW15-22 and PnNL2018B-use ACE2 as their receptor, with narrow ortholog specificity. Cryoelectron microscopy structures of the MOW15-22/PnNL2018B RBD-ACE2 complexes unveil an unexpected and entirely distinct binding mode, mapping >45 Å away from that of any other known ACE2-using coronaviruses. Functional profiling of ACE2 orthologs from 105 mammalian species led to the identification of host tropism determinants, including an ACE2 N432-glycosylation restricting viral recognition, and the design of a soluble P.nat ACE2 mutant with potent viral neutralizing activity. Our findings reveal convergent acquisition of ACE2 usage for merbecoviruses found in European bats, underscoring the extraordinary diversity of ACE2 recognition modes among coronaviruses and the promiscuity of this receptor.
Authors
- Zengqin Deng (ORCID: https://orcid.org/0000-0002-5658-2068)
- M. Alejandra Tortorici (ORCID: https://orcid.org/0000-0002-2260-2577)
- Huan Yan (ORCID: https://orcid.org/0000-0001-8744-8665)
- Fei Tong (ORCID: https://orcid.org/0000-0002-6035-608X)
- Cameron Stewart (ORCID: https://orcid.org/0000-0002-2786-6256)
- Jingjing Tang (ORCID: https://orcid.org/0000-0003-1447-5018)
- Young‐Jun Park (ORCID: https://orcid.org/0000-0003-2901-6949)
- Chengbao Ma
- Meiling Huang (ORCID: https://orcid.org/0000-0002-8766-9510)
- Jimin Lee (ORCID: https://orcid.org/0000-0001-5849-7732)
- Yuanmei Chen (ORCID: https://orcid.org/0000-0002-3804-731X)
- Daniel Asarnow (ORCID: https://orcid.org/0000-0001-7870-5308)
- David Veesler (ORCID: https://orcid.org/0000-0002-6019-8675)
- Jun-Yu Si
- Chen Liu (ORCID: https://orcid.org/0009-0003-0430-6146)
- Jing Li (ORCID: https://orcid.org/0000-0001-9588-5291)
- Peng Liu (ORCID: https://orcid.org/0000-0002-5164-088X)
- Jing Chen (ORCID: https://orcid.org/0000-0002-2872-3353)
- Zheng‐Li Shi (ORCID: https://orcid.org/0000-0001-8089-163X)
- Xiao Yang (ORCID: https://orcid.org/0000-0003-1246-7065)
- Yu Xiao (ORCID: https://orcid.org/0000-0002-3451-6625)
- Qing Xiong (ORCID: https://orcid.org/0000-0002-8656-2041)
- Jack Brown
- Ye-Hui Sun
Institutions
- Howard Hughes Medical Institute (US)
- Chinese Academy of Sciences (CN)
- University of Washington (US)
- Wuhan University (CN)
- Guangzhou Experimental Station (CN)
- Wuhan Institute of Virology (CN)
Publication Details
- Journal
- Cell
- Published
- 2025-02-07
- DOI
- https://doi.org/10.1016/j.cell.2024.12.031
- Citations
- 35
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 48.87
Funders
- Burroughs Wellcome Fund
- Arnold and Mabel Beckman Foundation
- National Natural Science Foundation of China
- Fudan University
- Natural Science Foundation of Hubei Province
- Tsinghua University
- National Health and Family Planning Commission of the People's Republic of China
- Wuhan University
- Hubei University
- National Institutes of Health
- Goddard Space Flight Center
- University of California, San Francisco
- Leibniz-Gemeinschaft
- Fundamental Research Funds for the Central Universities
- National Institute of Allergy and Infectious Diseases