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SARS-CoV-2 Coronavirus Variant Omicron cell delta on green background 2021 2022.

Omicron’s molecular structure could help explain its global takeover

Multiple studies are revealing why the SARS-CoV-2 variant is so transmissible, but also seems to cause milder disease.

After it was first detected in South Africa last November, Omicron spread around the globe faster than any previous variant of the coronavirus SARS-CoV-2, readily infecting even those who had been vaccinated or previously had COVID-19. To learn how it was able to do this, scientists have turned to techniques such as cryo-electron microscopy, to visualize Omicron’s molecular structure at near-atomic resolution.

By comparing the variant’s structure with that of the original version of SARS-CoV-2, they have begun to shed light on which features of the highly mutated virus have enabled it to evade the body’s immune defences, while also maintaining its ability to attack a person’s cells. And they’ve begun to unpick why Omicron seems to cause milder disease than previous variants.

“Omicron is very different structurally than all the other variants we have known so far,” says Priyamvada Acharya, a structural biologist at the Duke Human Vaccine Institute in Durham, North Carolina.

Evading immune defences

Omicron has dozens of mutations not seen in the original SARS-CoV-2 strain that researchers first detected in Wuhan, China. More than 30 of those mutations are in the spike protein on the coronavirus’s surface, which helps the virus to latch on to and infect host cells. No previous SARS-CoV-2 variant seems to have accumulated so many genetic changes. By comparison, the Delta and Alpha variants, dominant earlier in the pandemic, each have approximately ten mutations on their spike proteins.

Fifteen of Omicron’s spike mutations are found in the protein’s receptor binding domain (RBD), a region that binds to a receptor called ACE2 on a person’s cells to gain entry. A research team including David Veesler, a structural biologist at the University of Washington in Seattle, has shown1 that these changes, along with 11 mutations in a region of the spike called the N-terminal domain, have completely remodelled the areas of the protein that are recognized by ‘neutralizing’ antibodies. These antibodies are generated after a person receives a vaccine against SARS-CoV-2 or is infected; they later recognize the pathogen and prevent it from entering cells. The remodelling severely hinders the ability of most neutralizing antibodies to recognize the virus.

With such a big shift in shape, there’s a huge question over how Omicron can still bind strongly to ACE2. “Normally, when you have so many mutations all over, you expect that you will also have compromised the ability to bind the receptor,” says Sriram Subramaniam, a structural biologist at the University of British Columbia in Vancouver, Canada.

Subramaniam and his colleagues answered the question by demonstrating that although some of the mutations in Omicron’s RBD hinder its ability to bind to ACE2, others strengthen it2. For example, the K417N mutation disrupts a key salt bridge — a bond between oppositely charged bits of protein — that helps to link the spike protein to ACE2. A combination of other mutations, however, helps to form new salt bridges and hydrogen bonds that strengthen the link to ACE2. The net effect is that Omicron bonds to ACE2 more strongly than does the original version of SARS-CoV-2, and as strongly as the Delta variant.

Veesler and his colleagues have also found1 enhanced interactions between Omicron’s RBD and ACE2. Omicron has adopted a “very elegant molecular solution, where the mutations are mediating immune evasion while enhancing receptor binding”, Veesler says.

Martin Hällberg, a structural biologist at the Karolinska Institute in Stockholm, applauds the work by these groups, but points out that it’s an open question how some neutralizing antibodies can still detect Omicron. If researchers can understand the structural basis for that recognition, he adds, it might help to counter variants that emerge in future.

Lingering mysteries

Some structural studies have also provided possible explanations for another of Omicron’s properties: that it seems to have more difficulty infecting the lungs than the nose and throat. Some scientists say this might explain why Omicron seems to cause milder disease than other variants.

Many studies focus on two possible mechanisms by which SARS-CoV-2 and its variants might enter a person’s cells after binding to ACE2. The first involves an enzyme on host cells called TMPRSS2, which cleaves off a piece of the spike, exposing a region that embeds into the cells’ membranes; eventually, the virus fuses with the cells and injects its genetic material directly into them. The other, slower pathway involves the virus entering host cells through bubbles known as endosomes before releasing its contents.

Several groups have found evidence that Omicron prefers the slower route3. For example, Veesler and his colleagues found4 that cleavage of the spike protein, required for the TMPRSS2 pathway, was less efficient for Omicron than for Delta. The researchers also noted that there are higher levels of TMPRSS2 in the lungs than in the upper airways — possibly explaining Omicron’s preference for infecting the nose and throat.

But not everyone agrees that Omicron prefers this entry route. Bing Chen, a structural biologist at Harvard Medical School in Boston, Massachusetts, notes that some groups have reported evidence5 for a slightly different mechanism than either of the other two. He suggests instead that Omicron’s mildness is related to ACE2.

To bind to ACE2, the virus’s RBD needs to flip from a ‘down’ to an ‘up’ position. In a preprint6, Chen and his colleagues have reported evidence that Omicron’s RBD has difficulty moving into the ‘up’ conformation because of a structural change induced by one of its many mutations. As a result, Omicron requires higher levels of ACE2 to fuse with host cells than do other variants. “This could explain why Omicron doesn’t really infect the lung cells, because lung cells generally have much lower ACE2 levels compared to the cells in the upper respiratory tract,” Chen says. But further investigation is needed, he adds.

Open questions remain, but researchers are hoping to use structural knowledge about Omicron to help develop more effective treatments and vaccines against it — and against future variants of concern. “Omicron really redefines what we thought variants look like,” Veesler says.


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