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. 2023 Apr 5;19(4):e1011206.
doi: 10.1371/journal.ppat.1011206. eCollection 2023 Apr.

Cryo-EM structures and binding of mouse and human ACE2 to SARS-CoV-2 variants of concern indicate that mutations enabling immune escape could expand host range

Dongchun Ni  1   2 , Priscilla Turelli  3 , Bertrand Beckert  4 , Sergey Nazarov  4 , Emiko Uchikawa  4 , Alexander Myasnikov  4 , Florence Pojer  5 , Didier Trono  3 , Henning Stahlberg  1   2 , Kelvin Lau  5
Affiliations

Cryo-EM structures and binding of mouse and human ACE2 to SARS-CoV-2 variants of concern indicate that mutations enabling immune escape could expand host range

Dongchun Ni et al. PLoS Pathog. .

Abstract

Investigation of potential hosts of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is crucial to understanding future risks of spillover and spillback. SARS-CoV-2 has been reported to be transmitted from humans to various animals after requiring relatively few mutations. There is significant interest in describing how the virus interacts with mice as they are well adapted to human environments, are used widely as infection models and can be infected. Structural and binding data of the mouse ACE2 receptor with the Spike protein of newly identified SARS-CoV-2 variants are needed to better understand the impact of immune system evading mutations present in variants of concern (VOC). Previous studies have developed mouse-adapted variants and identified residues critical for binding to heterologous ACE2 receptors. Here we report the cryo-EM structures of mouse ACE2 bound to trimeric Spike ectodomains of four different VOC: Beta, Omicron BA.1, Omicron BA.2.12.1 and Omicron BA.4/5. These variants represent the oldest to the newest variants known to bind the mouse ACE2 receptor. Our high-resolution structural data complemented with bio-layer interferometry (BLI) binding assays reveal a requirement for a combination of mutations in the Spike protein that enable binding to the mouse ACE2 receptor.

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Conflict of interest statement

The authors declare no competing interests in regards to this work.

Figures

Fig 1
Fig 1. mACE2 and hACE2 binding to variants of concern.
(A) BLI binding assays of captured dimeric mouse ACE2 versus various concentrations of Spike variants of concern. Data curves are colored by concentration and the black line indicates the 1:1 fit of the data. (B) BLI binding assays of captured dimeric human ACE2 versus various concentrations of Spike variants of concern. Data curves are colored by concentration and the black line indicates the 1:1 fit of the data. (C) Sequence alignment of human ACE2 with mouse ACE2 and other selected species. Red boxes highlight critical differences between human and mouse ACE2 residues.
Fig 2
Fig 2. Cryo-EM structures of mACE2 bound to variants of concern.
(A) Cryo-EM densities of the full mACE2/Spike variant of concern complexes. Each protomer of the Spike trimer is colored separately with mACE2 colored in grey. (B) Focused refinement of the RBD-mACE2 interface of each complex as in (A). (C) Superposition of RBD-mACE2 complexes on to the BA.1-mACE2 complex show mACE2 binds similarly for all variants. (D) Superposition of the BA.4/5 RBD-hACE2 complex with the BA.4/5 RBD-mACE2 complex.
Fig 3
Fig 3. Cryo-EM structures of hACE2 bound to the BA.4/5 Spike.
(A) Cryo-EM densities of the full hACE2/BA.4/5 Spike. Each protomer of the Spike trimer is colored separately with hACE2 colored in light green. Inset shows focused refinement of the RBD-hACE2 interface. (B) Superposition of BA.4/5 RBD-hACE2 complex with the BA.1 RBD-hACE2 complex (PDB 7T9L).
Fig 4
Fig 4. Structural basis of mACE2 binding to variants of concern and of hACE2/BA.4/5.
(A) Zoomed view of the binding interface between mACE2 and RBD of variants of concern with cryo-EM densities. (B) Highlighted views of specific interaction sites of patch 1 and patch 2 as indicated in (A). (C) Zoomed view of the binding interface between hACE2 and RBD of variants of concern with cryo-EM densities with highlighted views of specific interaction sites.
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Grants and funding

D.N and H.S acknowledge funding by an NCCR (National Centre of Competence in Research) TransCure grant (185544) from the Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation). K.L and F.P were supported by core funding provided by the EPFL School of Life Sciences (SV). The funders had no role in the the study design, data collection and analysis, decision to publish or preparation of the manuscript.