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Once the viral spikes bind to ACE2, other proteins on the host cell’s surface initiate a process that leads to the merging of viral and cell membranes (see ‘Viral entry up close’).Īn animation of the way SARS-CoV-2 fuses with cells.
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The Delta variant, which is now spreading around the world, hosts multiple mutations in the S1 subunit, including three in the RBD that seem to improve the RBD’s ability to bind to ACE2 and evade the immune system 7. “It is helping the virus along by making it easier to enter into cells,” says Priyamvada Acharya, a structural biologist at the Duke Human Vaccine Institute in Durham, North Carolina, who is studying the spike mutations. The Alpha variant, for example, includes ten changes in the spike-protein sequence, which result in RBDs being more likely to stay in the ‘up’ position 6. (A second spike subunit, S2, prompts viral fusion with the host cell’s membrane.) Worrying variants of SARS-CoV-2 tend to have mutations in the S1 subunit of the spike protein, which hosts the RBDs and is responsible for binding to the ACE2 receptor. But compared with SARS-CoV, SARS-CoV-2 binds to ACE2 an estimated 2–4 times more strongly 4, because several changes in the RBD stabilize its virus-binding hotspots 5. This receptor is also the docking point for SARS-CoV, the virus that causes severe acute respiratory syndrome (SARS). Turoňová et al./ ScienceĮarly in the pandemic, researchers confirmed that the RBDs of SARS-CoV-2 spike proteins attach to a familiar protein called the ACE2 receptor, which adorns the outside of most human throat and lung cells. “That’s why it’s so difficult to control,” says Wendy Barclay, a virologist at Imperial College London.Ĭryo-electron tomography images of SARS-CoV-2 virions. These are some of the tools that have enabled the virus to spread so quickly and claim millions of lives. Later, as it leaves cells, SARS-CoV-2 executes a crucial processing step to prepare its particles for infecting even more human cells.
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Scientists have discovered key adaptations that help the virus to grab on to human cells with surprising strength and then hide itself once inside. What has emerged from 19 months of work, backed by decades of coronavirus research, is a blow-by-blow account of how SARS-CoV-2 invades human cells (see ‘Life cycle of the pandemic coronavirus’). By picking apart the infection process, they hope to find better ways to interrupt it through improved treatments and vaccines, and learn why the latest strains, such as the Delta variant, are more transmissible.
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Since the start of the COVID-19 pandemic, scientists have been developing a detailed understanding of how SARS-CoV-2 infects cells. It’s possible that snipping out those two sugars could reduce the virus’s infectivity, says Amaro, although researchers don’t yet have a way to do this. McLellan’s team built a way to try the same experiment in the lab, and by June 2020, the collaborators had reported that mutating the two glycans reduced the ability of the spike protein to bind to a human cell receptor 1 - a role that no one has previously recognized in coronaviruses, McLellan says. When Amaro mutated the glycans in the computer model, the RBD collapsed. In Amaro’s simulation, when the RBD lifted up above the glycan cloud, two glycans swooped in to lock it into place, like a kickstand on a bicycle. Source: Structural image from Lorenzo Casalino, Univ. But ten minutes later, structural biologist Jason McLellan at the University of Texas at Austin chimed in: the uncoated loop was a receptor binding domain (RBD), one of three sections of the spike that bind to receptors on human cells (see ‘A hidden spike’). Within an hour, one researcher asked in a comment: what was the naked, uncoated loop sticking out of the top of the protein?Īmaro had no idea. On 22 March 2020, she posted the simulation to Twitter. But last year, Amaro’s laboratory group and collaborators created the most detailed visualization yet of this coat, based on structural and genetic data and rendered atom-by-atom by a supercomputer. Many viruses have glycans covering their outer proteins, camouflaging them from the human immune system like a wolf in sheep’s clothing. “When you see it with all the glycans, it’s almost unrecognizable,” says Amaro, a computational biophysical chemist at the University of California, San Diego. It was swathed in sugar molecules, known as glycans. “It’s striking,” thought Rommie Amaro, staring at her computer simulation of one of the trademark spike proteins of SARS-CoV-2, which stick out from the virus’s surface. The coronavirus sports a luxurious sugar coat. A computer simulation of the structure of the coronavirus SARS-CoV-2.