Scientists demonstrate how COVID-19 infects human cells

Researchers have used cryogenic electron microscopy to show that coronaviruses enter human cells through an interaction with angiotensin-converting enzyme 2 (ACE2).

COVID-19 has been shown to bind to ACE2 via the S protein on its surface. During infection, the S protein is cleaved into subunits, S1 and S2. S1 contains the receptor binding domain (RBD) which allows coronaviruses to directly bind to the peptidase domain (PD) of ACE2. S2 then likely plays a role in membrane fusion.

Chinese researchers have now used cryogenic electron microscopy (cryo-EM) to study the structure of the ACE2 when it is bound to one of its typical ligands, the amino acid transporter B0AT1 and also how the COVID-19 RBD may bind to the ACE2-B0AT1 complex. These structures have previously not been identified and could aid in producing antivirals or a vaccine that can block coronavirus infection by targeting ACE2.

The paper, published in Science, suggests ACE2 needs to dimerise to be active. The resultant homodimer has two PDs, able to bind two COVID-19 S protein trimers simultaneously.

A previous study found COVID-19 S proteins form trimers with two of the RBDs facing one direction (down) and the other facing the opposite way (up).

In the current study, the team identified that the structures could only bind if the PD interacts with the up RBD.

Fig : Side and top views of the pre-fusion structure of the COVID-19 S protein with a single RBD in the up conformation. The two RBD-down protomers are shown as cryo-EM density in either white or grey and the RBD-up protomer is shown in ribbons coloured green (credit: adapted from Wrapp, D, et al.).

Fig : The overall structure of the RBD-ACE2-B0AT1 complex. (A) Cryo-EM map of the RBD-ACE2-B0AT1 complex. Left: Overall reconstruction of the ternary complex at 2.9 Å. Inset: focused refined map of RBD. (B) Overall structure of the RBD-ACE2-B0AT1 complex. The complex is coloured by subunits, with the protease domain (PD) and the Collectrin-like domain (CLD) coloured cyan and blue in one of the ACE2 protomers, respectively. The glycosylation moieties are shown as sticks (credit: Yan, R et al.).

They further compared how SARS-CoV-2-RBD binding is different to other SARS-CoV-RBDs binding; showing that some changes in the sequence may make associations tighter in COVID-19, while others could reduce the binding affinity.

The researchers concluded that their research could contribute to structure-based designs of decoy ligands or antibodies able to specifically target ACE2 or coronavirus spike proteins to prevent viral infection.

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