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

Wei Zhang1,2, Ke Shi3, Qibin Geng1,2

  • 1Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455.

Proceedings of the National Academy of Sciences of the United States of America
|October 18, 2022
PubMed
Summary

The omicron variant

Keywords:
COVID-19X-ray crystallographymouse angiotensin-converting enzyme 2omicron variantreceptor-binding domain (RBD)

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Area of Science:

  • Virology
  • Molecular Biology
  • Evolutionary Biology

Background:

  • The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) omicron variant rapidly emerged and spread globally.
  • Understanding the animal reservoir and evolutionary origins of SARS-CoV-2 variants is crucial for public health.
  • The receptor-binding domain (RBD) of SARS-CoV-2 is a key determinant of host cell entry and viral adaptation.

Purpose of the Study:

  • To investigate the impact of key omicron variant mutations on the binding affinity to human and mouse angiotensin-converting enzyme 2 (ACE2).
  • To determine the structural basis for omicron RBD recognition of mouse ACE2.
  • To explore the potential role of mouse ACE2 adaptation in the evolutionary origin of the omicron variant.

Main Methods:

  • Analysis of four specific mutations (Q493R, Q498R, N501Y, Y505H) in the omicron RBD.
  • Assessment of RBD binding affinity to human and mouse ACE2.
  • Determination of the crystal structure of the omicron RBD complexed with mouse ACE2.

Main Results:

  • All four investigated omicron mutations enhanced the RBD's affinity for mouse ACE2, with variable effects on human ACE2 affinity.
  • The crystal structure revealed that three mutations (Q493R, Q498R, Y505H) are uniquely adapted to mouse ACE2, while N501Y is adapted to both human and mouse ACE2.
  • These findings indicate significant adaptation of the omicron RBD to mouse ACE2 prior to human infection.

Conclusions:

  • The omicron variant's RBD exhibits substantial pre-adaptation to mouse ACE2.
  • This adaptation to mouse ACE2 provides critical insights into the potential evolutionary trajectory and origin of the omicron variant.
  • The study highlights the importance of considering animal reservoirs in the emergence and evolution of SARS-CoV-2 variants.