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).
Scientists exploring how coronaviruses like COVID-19 infect human cells have shown that the SARS-CoV-2 spike (S) glycoprotein binds to the cell membrane protein angiotensin-converting enzyme 2 (ACE2) to enter human cells.
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.
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.