A SARS-CoV-2 infection begins when the virus’s spike proteins bind to ACE2 cell surface receptors, enabling the virus to infect human cells. This key event of the receptor binding is followed by fusion of the virus and cell membranes to release the virus genome into the cell. However, the exact nature of the ACE2 binding to the SARS-CoV-2 spike remains unknown. New research uncovers new biology regarding the binding, including that the spike can adopt at least ten distinct structural states, when in contact with the human virus receptor ACE2.

This new work into the mechanism, that will equip research groups with the understanding needed to inform studies into vaccines and treatments, was published in Nature in the paper, “Receptor binding and priming of the spike protein of SARS-CoV-2 for membrane fusion.

In the first study to examine the binding mechanism between ACE2 and the spike protein in its entirety, researchers in the Crick’s Structural Biology of Disease Processes Laboratory, have characterized ten distinct structures that are associated with different stages of receptor binding and infection.

“By examining the binding event in its entirety, we’ve been able to characterize spike structures that are unique to SARS-CoV-2,” said Donald Benton, PhD, postdoctoral fellow in the Structural Biology of Disease Processes Laboratory at the Crick. “We can see that as the spike becomes more open, the stability of the protein will reduce, which may increase the ability of the protein to carry out membrane fusion, allowing 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 spike glycoprotein is post-translationally cleaved, as are other class I membrane fusion proteins (in this case by furin) into S1 and S2 components that remain associated following cleavage. The authors noted that fusion activation following receptor binding is proposed to involve the exposure of a second proteolytic site (S2’), cleavage of which is required for the fusion peptide release. Specifically, the team investigated the binding of ACE2 to the furin-cleaved form of SARS-CoV-2 S by cryoEM. The authors also noted that the ten different molecular species classified include the unbound, closed spike trimer, the fully open ACE2-bound trimer, and dissociated monomeric S1 bound to ACE2.

The researchers hope that the more that can be uncovered about how SARS-CoV-2 differs from other coronaviruses, the more targeted we can be with the development of new treatments and vaccines.

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

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

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