New Insight into Structural Mechanism of Coronavirus Receptor Binding to Aid Development of COVID-19 Treatments and Vaccines

The infection begins when a spike protein binds with ACE2 cell surface receptors and, at later stages, catalyses the release of the virus genome into the cell. However, the exact nature of the ACE2 binding to the SARS-CoV-2 spike remains unknown. Researchers from the Francis Crick Institute (London, UK) have now found that the spike protein on the surface of the SARS-CoV-2 coronavirus can adopt at least 10 distinct structural states, when in contact with the human virus receptor ACE2.

In the first study to examine the binding mechanism between ACE2 and the spike protein in its entirety, the researchers have characterized 10 distinct structures that are associated with different stages of receptor binding and infection. The team incubated a mixture of spike protein and ACE2 before trapping different forms of the protein by rapid freezing in liquid ethane. They examined these samples using cryo-electron microscopy, obtaining tens of thousands of high-resolution images of the different binding stages. They observed that the spike protein exists as a mixture of closed and open structures., Following ACE2 binding at a single open site, the spike protein becomes more open, leading to a series of favorable conformational changes, priming it for additional binding. Once the spike is bound to ACE2 at all three of its binding sites, its central core becomes exposed, which may help the virus to fuse to the cell membrane, permitting infection. The researchers hope that the more they can uncover about how SARS-CoV-2 differs from other coronaviruses, the more targeted they can be with the development of new treatments and vaccines. The team continues to examine the structures of spikes of SARS-CoV-2 and related coronaviruses in other species to better understand the mechanisms of viral infection and evolution.

“As we unravel the mechanism of the earliest stages of infection, we could expose new targets for treatments or understand which currently available anti-viral treatments are more likely to work,” said Antoni Wrobel, co-lead author and postdoctoral training fellow in the Structural Biology of Disease Processes Laboratory at the Crick.

“There’s so much we still don’t know about SARS-CoV-2, but its basic biology contains the clues to managing this pandemic,” said Steve Gamblin, group leader of the Structural Biology of Disease Processes Laboratory at the Crick. “By understanding what makes this virus distinctive, researchers could expose weaknesses to exploit.”

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Francis Crick Institute