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Posts Tagged ‘D614G mutation’

Cryo-EM disclosed how the D614G mutation changes SARS-CoV-2 spike protein structure.

Reporter: Dr. Premalata Pati, Ph.D., Postdoc

SARS-CoV-2, the virus that causes COVID-19, has had a major impact on human health globally; infecting a massive quantity of people around 136,046,262 (John Hopkins University); causing severe disease and associated long-term health sequelae; resulting in death and excess mortality, especially among older and prone populations; altering routine healthcare services; disruptions to travel, trade, education, and many other societal functions; and more broadly having a negative impact on peoples physical and mental health.

It’s need of the hour to answer the questions like what allows the variants of SARS-CoV-2 first detected in the UK, South Africa, and Brazil to spread so quickly? How can current COVID-19 vaccines better protect against them?

Scientists from the Harvard Medical School and the Boston Children’s Hospital help answer these urgent questions. The team reports its findings in the journal “Science a paper entitled Structural impact on SARS-CoV-2 spike protein by D614G substitution. The mutation rate of the SARS-CoV-2 virus has rapidly evolved over the past few months, especially at the Spike (S) protein region of the virus, where the maximum number of mutations have been observed by the virologists.

Bing Chen, HMS professor of pediatrics at Boston Children’s, and colleagues analyzed the changes in the structure of the spike proteins with the genetic change by D614G mutation by all three variants. Hence they assessed the structure of the coronavirus spike protein down to the atomic level and revealed the reason for the quick spreading of these variants.


This model shows the structure of the spike protein in its closed configuration, in its original D614 form (left) and its mutant form (G614). In the mutant spike protein, the 630 loop (in red) stabilizes the spike, preventing it from flipping open prematurely and rendering SARS-CoV-2 more infectious.

Fig. 1. Cryo-EM structures of the full-length SARS-CoV-2 S protein carrying G614.

(A) Three structures of the G614 S trimer, representing a closed, three RBD-down conformation, an RBD-intermediate conformation and a one RBD-up conformation, were modeled based on corresponding cryo-EM density maps at 3.1-3.5Å resolution. Three protomers (a, b, c) are colored in red, blue and green, respectively. RBD locations are indicated. (B) Top views of superposition of three structures of the G614 S in (A) in ribbon representation with the structure of the prefusion trimer of the D614 S (PDB ID: 6XR8), shown in yellow. NTD and RBD of each protomer are indicated. Side views of the superposition are shown in fig. S8.

IMAGE SOURCE: Bing Chen, Ph.D., Boston Children’s Hospital, https://science.sciencemag.org/content/early/2021/03/16/science.abf2303

The work

The mutant spikes were imaged by Cryo-Electron microscopy (cryo-EM), which has resolution down to the atomic level. They found that the D614G mutation (substitution of in a single amino acid “letter” in the genetic code for the spike protein) makes the spike more stable as compared with the original SARS-CoV-2 virus. As a result, more functional spikes are available to bind to our cells’ ACE2 receptors, making the virus more contagious.


Fig. 2. Cryo-EM revealed how the D614G mutation changes SARS-CoV-2 spike protein structure.

IMAGE SOURCE:  Zhang J, et al., Science

Say the original virus has 100 spikes,” Chen explained. “Because of the shape instability, you may have just 50 percent of them functional. In the G614 variants, you may have 90 percent that is functional. So even though they don’t bind as well, the chances are greater and you will have an infection

Forthcoming directions by Bing Chen and Team

The findings suggest the current approved COVID-19 vaccines and any vaccines in the works should include the genetic code for this mutation. Chen has quoted:

Since most of the vaccines so far—including the Moderna, Pfizer–BioNTech, Johnson & Johnson, and AstraZeneca vaccines are based on the original spike protein, adding the D614G mutation could make the vaccines better able to elicit protective neutralizing antibodies against the viral variants

Chen proposes that redesigned vaccines incorporate the code for this mutant spike protein. He believes the more stable spike shape should make any vaccine based on the spike more likely to elicit protective antibodies. Chen also has his sights set on therapeutics. He and his colleagues are further applying structural biology to better understand how SARS-CoV-2 binds to the ACE2 receptor. That could point the way to drugs that would block the virus from gaining entry to our cells.

In January, the team showed that a structurally engineered “decoy” ACE2 protein binds to SARS-CoV-2 200 times more strongly than the body’s own ACE2. The decoy potently inhibited the virus in cell culture, suggesting it could be an anti-COVID-19 treatment. Chen is now working to advance this research into animal models.

Main Source:

Abstract

Substitution for aspartic acid by glycine at position 614 in the spike (S) protein of severe acute respiratory syndrome coronavirus 2 appears to facilitate rapid viral spread. The G614 strain and its recent variants are now the dominant circulating forms. We report here cryo-EM structures of a full-length G614 S trimer, which adopts three distinct prefusion conformations differing primarily by the position of one receptor-binding domain. A loop disordered in the D614 S trimer wedges between domains within a protomer in the G614 spike. This added interaction appears to prevent premature dissociation of the G614 trimer, effectively increasing the number of functional spikes and enhancing infectivity, and to modulate structural rearrangements for membrane fusion. These findings extend our understanding of viral entry and suggest an improved immunogen for vaccine development.

https://science.sciencemag.org/content/early/2021/03/16/science.abf2303?rss=1

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Coronavirus mutation-does it matter?

Reporter : Irina Robu, PhD

Soon after SARS-CoV-2 was detected in China, scientists began analyzing viral sample and posting the genetic codes online. Mutations allowed researchers to track the spread by linking closely related viruses to understand how SARS-CoV-2 infects humans.  They recognized that SARS-CoV-2 encode their genome in RNA and tends to pick up mutations quickly as they are copied inside their hosts.  Yet,  sequencing data suggest that coronaviruses change more slowly than most RNA viruses, probably because of a proofreading enzyme that corrects fatal copying mutations.  In spite of the virus slow mutation rate, scientists have been able to classified more than 12,000 mutations in SARS-CoV-2 genomes.

Many scientists such as David Montefiori, a virologist who spent much of his career studying how chance mutations in HIV helps it evade the immune system thought that COVID-19 might cause the same thing.  His laboratory in collaboration with Dr. Bette Korber investigated several thousands of coronavirus sequences for mutations that might have changed virus properties around the world.

Compared to HIV, SARS-CoV-2 seems to be changing slower than it spreads, but one mutation is obvious. That mutation  includes a gene encoding the spike protein, which helps the virus particles penetrate cells. According to Korber, the 614th amino acid position of the spike protein, the amino acid aspartate was replaced by glycine, because of a mutation, D614G that altered a single nucleotide in the virus’s 29,903-letter RNA code.

To observe whether D614G  mutation made the virus more transmissible, Montefiori evaluated its effects under laboratory conditions but he couldn’t study the natural SARS-CoV-2 virus in his lab, because of the biosafety containment required. So, he studied a genetically modified form of HIV that used the SARS-CoV-2 spike protein to infect cells. Such ‘pseudo virus’ particles are a workhorse of virology labs: they enable the safe study of deadly pathogens such as the Ebola virus, and they make it simpler to test the effects of mutations.

The strongest sign that D614G has a consequence on the spread of SARS-CoV-2 in humans comes from an ambitious UK effort called the COVID-19 Genomics UK Consortium, which has analyzed genomes of around 25,000 viral samples. From these data, researchers have identified more than 1,300 instances in which a virus entered the United Kingdom and spread, including examples of D- and G-type viruses.

What is clearly known is that D614G is an adaptation that helps the virus infect cells or compete with viruses that don’t carry the change, while at the same time altering a bit of information about how SARS-CoV-2 spreads between people and through a population.  Some scientists believe that D614G mutation should explain how SARS-CoV-2 fuses with cells and can use that process to develop a more efficient vaccine. 

At the present time, the evidence suggests that D614G doesn’t stop the immune system’s neutralizing antibodies from recognizing SARS-CoV-2, partly because the mutation is not in the spike protein’s receptor-binding domain.

SOURCE

https://www.nature.com/articles/d41586-020-02544-6?utm_source=Nature+Briefing

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