Scientists explore structure of SARS-CoV-2 receptor-binding domain with G485R mutation

By Angela Betsaida B. Laguipo, BSNMar 18 2021

The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to spread globally, with new variants of concern continuing to emerge.

Scientists aim to closely monitor the spread of the virus and detect newly emerging variants that may undermine vaccines and therapies or increase viral transmissibility. Three variants of concern have been actively spreading over the last few months: the U.K. Variant, the South Africa Variant, and the Brazilian Variant.

Study: SARS-CoV-2 Spike receptor-binding domain with a G485R mutation in complex with human ACE2. Image Credit: Design_Cells / Shutterstock

*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Researchers 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.

The G485R mutation

Found 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.

The spike (or S) protein is a vital antigenic target, as it is the most accessible part of the virus’s architecture.

Mutations in the coronavirus's structural proteins play a pivotal role in determining virulence and the virus's ability to escape the host’s immune system response.

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. The E484K mutation has been observed to contribute to antigenic escape.

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 study

In the study, published in the pre-print server bioRxiv*, 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.

Now, the 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.

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 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.

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.  

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.

To date, vaccine rollouts have started in most countries. The distribution of vaccines to as many countries as possible in the shortest time is crucial to combat the spreading virus.

Currently, there have been more than 121.37 million cases of COVID-19 globally since the pandemic first emerged. Of these, 2.68 million people have died.

*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.