University of Melbourne Study Shows That G485R Mutation On SARS-CoV-2 Variants Plays A Vital Role In Evading Neutralizing Antibodies
Source: G485R Mutation Mar 19, 2021 3 years, 9 months, 5 days, 19 hours, 58 minutes ago
As new SARS-CoV-2 coronavirus variants are fast emerging and spreading globally, threatening to change the course of the COVID-19 pandemic, scientist are now turning to studying each and every one of these new mutations found on the various variants to better understand the effects of these mutations.
Researchers from the University of Melbourne in a new study found that the
G485R mutation on S-CoV-2 variants plays a vital role in evading the immune system's neutralizing antibodies.
Ever since SARS-CoV-2 emerged in 2019, genomic sequencing has identified mutations in the viral RNA including in the receptor-binding domain of the Spike protein.
Structural characterization of the Spike carrying point mutations aids in the understanding of how these mutations impact binding of the protein to its human receptor, ACE2, and to therapeutic antibodies.
Importantly the Spike G485R mutation has been observed in multiple isolates of the virus and mutation of the adjacent residue E484 to lysine is known to contribute to antigenic escape. Here, the study team crystallized the SARS-CoV-2 Spike receptor-binding domain with a G485R mutation in complex with human ACE2. The crystal structure shows that while the G485 residue does not have a direct interaction with ACE2, its mutation to arginine affects the structure of the loop made by residues 480-488 in the receptor-binding motif, disrupting the interactions of neighboring residues with ACE2 and with potential implications for antigenic escape from vaccines, antibodies and other biologics directed against SARS-CoV-2 Spike.
The study findings were published on a preprint server and are currently being peer reviewed.
https://www.biorxiv.org/content/10.1101/2021.03.16.434488v1
At present numerous researchers are aiming to closely monitor the spread of the virus and detect newly emerging variants that may undermine vaccines and therapies or increase viral transmissibility.
To date, four variants of concern have been actively spreading over the last few months: the U.K. Variant, the South Africa Variant, the Brazilian Variant and the Californian Variant.
Scientists at the Bio21 Institute and Department of Biochemistry and Pharmacology, The University of Melbourne, studied the structure of a SARS-CoV-2 spike receptor-binding domain (RBD) with a G485R mutation. This mutation is a residue and not directly involved in interactions with the angiotensin-converting enzyme 2 (ACE2) residues but found in the Β1´/Β2' loop region.
Located on the virus's spike protein, the receptor-binding domain (RBD) is responsible for binding with the human cell angiotensin-converting enzyme 2 (ACE2) receptor. When these two bind, the virus is able to infiltrate the host cell’s metabolic machinery and commences viral replication.
Importantly the spike (or S) protein is a vital antigenic target, as it is the most accessible part of the virus’s architecture.
It is known that mutations in the coronavirus's structural proteins play a pivotal role in determining virulence and the virus's ability to escape the host&
;rsquo;s immune system response.
Although the G485 residue is not directly involved in interactions with ACE2 residues, but it is found in the the Β1´/Β2' loop region of the RBD motif. Its neighboring residue, E484 has gained the interest of the scientific community.
To date, the E484K mutation has been observed to contribute to antigenic escape.
Typically viruses may evolve by continuously mutating. It is crucial for the scientific community to study the correlation between mutation and the functions of viral proteins to develop effective vaccines and therapies that can keep up.
The researchers studied the G485R mutation on spike function. Previous studies have shown that G485R mutation reduces viral neutralization in some convalescent plasma up to five-fold.
The study team aimed to determine the structure of the G485R spike RBD on complex ACE2. They observed the mutation in many isolates of the virus, with the adjacent residue E484 to lysine is known to influence antigenic escape.
In order to arrive at the study findings, the team crystallized the SARS-CoV-2 spike receptor-binding domain with a G485R mutation in human ACE2.
The study team found that while the G485 residue does not directly interact with human ACE2, its mutation affects the receptor-binding motif's 480-488 loop structure.
Significantly this could lead to disruptions in other residues with ACE2, with possible implications for an antigenic escape from monoclonal antibodies against the SARS-CoV-2 spike.
The study findings and evidence also showed that G485R also plays a vital role in evading the immune system's neutralizing antibodies isolated from SARS-CoV-2 convalescent patients. This could help scientists develop vaccines that could target all the mutations to provide full and multivalent protection against COVID-19.
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