OmniVira

Structural basis for mouse receptor recognition by SARS-CoV-2 omicron variant.

Wei Zhang1,2 Ke Shi3 Qibin Geng1,2 Gang Ye1,2 Hideki Aihara3 Fang Li1,2
Affiliations 3 institutions
  1. Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455.
  2. Center for Coronavirus Research, University of Minnesota, Minneapolis, MN 55455.
  3. Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455.
PMID36256797 DOI10.1073/pnas.2206509119 Year2022 Journal Proceedings of the National Academy of Sciences of the United States of America Proc Natl Acad Sci U S A Languageeng Statusppublish

Abstract

The sudden emergence and rapid spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) omicron variant has raised questions about its animal reservoir. Here, we investigated receptor recognition of the omicron's receptor-binding domain (RBD), focusing on four of its mutations (Q493R, Q498R, N501Y, and Y505H) surrounding two mutational hotspots. These mutations have variable effects on the RBD's affinity for human angiotensin-converting enzyme 2 (ACE2), but they all enhance the RBD's affinity for mouse ACE2. We further determined the crystal structure of omicron RBD complexed with mouse ACE2. The structure showed that all four mutations are viral adaptations to mouse ACE2: three of them (Q493R, Q498R, and Y505H) are uniquely adapted to mouse ACE2, whereas the other one (N501Y) is adapted to both human ACE2 and mouse ACE2. These data reveal that the omicron RBD was well adapted to mouse ACE2 before omicron started to infect humans, providing insight into the potential evolutionary origin of the omicron variant.

Supporting text Virus Host Location
COVID-19 467 mouse angiotensin-converting enzyme 2 1 omicron variant 7 receptor-binding domain (RBD) 4 X-ray crystallography 5 Angiotensin-Converting Enzyme 2 177 COVID-19 425 Animals 1948 Humans 1440 Mice 253 Mutation 209 Peptidyl-Dipeptidase A 57 Protein Binding 193 SARS-CoV-2 453 Spike Glycoprotein, Coronavirus 274 SARS-CoV-2 variants 86 spike protein, SARS-CoV-2 157

Evidence records

2 total
Functional Mechanism
1 records · 1 evidence types
Evidence type Molecular Adaptation
1 records
OVE6443 Molecular Adaptation
Key finding

Structural analysis shows that four RBD mutations in the SARS-CoV-2 omicron variant (Q493R, Q498R, N501Y, and Y505H) represent viral adaptations enhancing binding to mouse ACE2, with N501Y adapted to both human and mouse ACE2.

Virus
Severe acute respiratory syndrome coronavirus 2
Host
Not specified
Location
Not specified
Supporting text

The structure showed that all four mutations are viral adaptations to mouse ACE2: three of them (Q493R, Q498R, and Y505H) are uniquely adapted to mouse ACE2, whereas the other one (N501Y) is adapted to both human ACE2 and mouse ACE2.

Genes or proteins
RBD | ACE2
Receptors
ACE2
Host factors
mouse ACE2 | human ACE2
Mutations
Q493R | Q498R | N501Y | Y505H
Mechanism types
receptor binding | receptor usage | host-range expansion
Genomic Evolution
1 records · 1 evidence types
Evidence type Phylogenetic Evolution
1 records
OVE6444 Phylogenetic Evolution
Key finding

Phylogenetic and structural analysis indicates that the SARS-CoV-2 omicron variant evolved adaptations to mouse ACE2 before infecting humans, suggesting a possible mouse-associated evolutionary origin.

Virus
Severe acute respiratory syndrome coronavirus 2
Host
house mouse Mus musculus Natural host human Homo sapiens Natural host
Location
Not specified
Supporting text

These data reveal that the omicron RBD was well adapted to mouse ACE2 before omicron started to infect humans, providing insight into the potential evolutionary origin of the omicron variant.

Genes or proteins
RBD | ACE2
Analysis methods
structural analysis | comparative sequence analysis