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Structural variations in human ACE2 may influence its binding with SARS-CoV-2 spike protein
Mushtaq Hussain1, Nusrat Jabeen2, Fozia Raza1
1Bioinformatics and Molecular Medicine Research Group, Dow Research Institute of Biotechnology and Biomedical Sciences, Dow College of Biotechnology, Dow University of Health Sciences, Karachi, Pakistan.
Journal of Medical Virology
|April 7, 2020
Summary
Genetic variations in human ACE2, the receptor for SARS-CoV-2, may influence COVID-19 susceptibility. Specific ACE2 variants, like rs73635825 and rs143936283, show altered interactions with the virus spike protein, suggesting potential resistance mechanisms.
Area of Science:
- Virology
- Genetics
- Structural Biology
Background:
- The COVID-19 pandemic, caused by SARS-CoV-2, poses a significant global health threat.
- Human Angiotensin-Converting Enzyme 2 (ACE2) is the primary receptor for the SARS-CoV-2 spike protein, mediating viral entry.
- Genetic variations in host ACE2 may influence susceptibility or resistance to SARS-CoV-2 infection.
Purpose of the Study:
- To investigate the structural basis of SARS-CoV-2 spike protein binding to different human ACE2 allelic variants.
- To identify specific ACE2 genetic variations that could impact viral interaction and infection susceptibility.
Main Methods:
- Selection of human ACE2 coding variants at reported spike protein binding sites.
- Homology modeling to construct molecular models of ACE2 variants.
- Superposition of variant models with native ACE2 and ACE2-spike protein complex to analyze structural changes and intermolecular interactions.
Main Results:
- Most ACE2 variants exhibited similar binding affinities to the SARS-CoV-2 spike protein compared to wild-type.
- Specific ACE2 alleles, rs73635825 (S19P) and rs143936283 (E329G), displayed notable alterations in intermolecular interactions with the spike protein.
- Variations in the spatial orientation of key interacting residues were observed in ACE2 variants.
Conclusions:
- ACE2 allelic variants can structurally influence interactions with the SARS-CoV-2 spike protein.
- Certain ACE2 variants may confer a degree of resistance to SARS-CoV-2 infection.
- This study provides a structural foundation for understanding host genetic factors in COVID-19 pathogenesis.
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