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Biochemistry

Researchers in China report structure of the novel coronavirus bound to its human target

The structure shows the first steps of SARS-CoV-2 infection, and could help in drug discovery

by Megha Satyanarayana
March 6, 2020

20200305lnp2-coronavirus.jpg
This cryogenic electron microscopy structure reveals the chemical interactions between the novel coronavirus and its target protein on human cells.

In another step toward developing treatments and vaccines against the novel coronavirus, SARS-CoV-2, a team of researchers in China have reported the crystal structure of a part of the virus bound to its target on human cells (Science, 2020. DOI: 10.1126/science.abb2762.

The snapshot of this interaction, captured through cryogenic electron microscopy by Qiang Zhou of the Westlake Institute for Advanced Study and colleagues, reveals some of the chemistry behind how the coronavirus hijacks angiotensin converting enzyme (ACE2), an enzyme involved in blood pressure regulation. The researchers think that the structure could lead to the development of antibodies that block this interaction.

The new cryo-EM structure comes hot on the heels of another revealed in February that showed the full viral spike protein, which is the part of the virus that binds ACE2 (Science, 2020. DOI: 10.1126/science.abb2507). Jason McLellan, the University of Texas at Austin researcher who led the team behind the spike protein structure, says that Zhou’s team’s work will help scientists better understand how coronaviruses have evolved to use this critical enzyme to get into human cells. He also agrees that the interaction captured in the structure could inspire the development of neutralizing antibodies. McLellan’s work with the coronavirus spike protein is being developed into a vaccine.

ACE2 is the first in a string of enzymes that convert the hormone angiotensin into its active form. When cleaved by enzymes, angiotensin makes blood vessels contract. The SARS-CoV-2 spike protein has two key elements involved in infecting human cells. A string of amino acids in the S1 subunit directly binds to the protein-cleaving part of ACE2 called the peptidase domain. The S2 subunit of the spike protein helps the virus fuse to the human cell. The new structure shows the first of these two events.

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“You have attachment, and entry. Blocking either function can prevent entry,” McLellan says, describing how treatments could be designed to stop SARS-CoV-2. “Ideally, you want antibodies that can target both functions.”

The ACE2 protein has a section that winds through the cell membrane, and that section has been difficult to crystallize. To overcome this, Zhou and his team paired it with another protein, an amino acid transporter, that it interacts with in cells. Once the researchers crystallized the ACE2 complex, they added a portion of the spike protein’s S1 subunit called the receptor binding domain. It’s not clear if that amino acid transporter plays any role in coronavirus infection.

The scientists found that the protein-cleaving part of ACE2 binds the spike through polar interactions formed from a bridge-like structure on the enzyme. Both ends of the receptor binding domain stick to ACE2 through hydrogen bonding and van der Waals forces, and in the middle, Zhou describes several amino acids that interact with an asparagine and histidine in ACE2 that may be required for the spike protein-ACE2 interaction to occur.

McLellan says that SARS-CoV-2 binds ACE2 more strongly than does the virus that caused the severe acute respiratory syndrome outbreak in 2003. Zhou’s research shows the subtle amino acid changes that create salt bridges and improve van der Waals interactions that might underlie this stronger interaction, he says.

Efforts to repurpose ACE2 inhibitors to block coronavirus infection have not been successful in the past, and McLellan says that given what has been revealed in this structure, it would be hard to develop a small molecule inhibitor that could squeeze between the virus and ACE2. Neutralizing antibodies, he says, might be a better bet.

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Comments
Donald Russell (March 15, 2020 6:22 PM)
Quite interesting coverage, incites one to learn more the biochemistry of this dangerous virus, and this may inspire researchers to pursue therapeutic tuldargets they would otherwise not have considered. Nicely done.
Colin Aitken (March 17, 2020 12:17 PM)
This is not a crystal structure (as it is described in the first paragraph) and the link to the article is broken. in addition, you cite the work as having been done by the corresponding author, which is erroneous or at the very least unclear.
Doug Beight (March 18, 2020 6:05 PM)
One would think that an appropriately designed bidentate ligand that binds the asparagine and the histidine moieties of ACE2 could be useful in disrupting the spike protein-ACE2 interaction. An alternative would be to find the corresponding interactions for the spike protein. The size of the molecule isn't important if you can tie up the binding sites of either of the interacting partners before they see each other. Knowing the conformations of the proteins at the binding site should allow one to do an in silico screen of appropriate structures which might then be tested in binding assays.
Favour Kalu (March 20, 2020 1:23 PM)
From the little background we were taught then , lysosome is an enzyme that spilts RNA. From what u post and there findings since the activation of COVID is triggered by lysosomal protease because every protein is coated in which it’s RNA is encapsulated in the coating and for it to be activated that coating has to be removed (which is the function of the lysosomal protease ).
I feel the aim is to prevent that from happening and since chloroquine can inhibit that process then it won’t be bad to be using it fir the mean time.
Dr. Suraj gupta (March 27, 2020 8:23 AM)
Novel corona virus loss infective at stomach because various pectolytic enzymes ...... Spike is loss
Robert Kern (March 28, 2020 3:19 PM)
Do you think a protein blocker would help prevent the virus from attaching to the human cells?
POORAN CHANDRA (March 30, 2020 10:38 AM)
If we break spike Protien or e-Protien of this virus we break the chain of the virus
Uchenna Cixtus Chukwuemeka (March 31, 2020 7:36 AM)
From the reports above,we understand that there are weak interactions between the s-protein of the virus and ACE2 protein,if an enzyme can be synthesize with the same conformational structure as the ACE2 protein that would bind strongly and have strong affinity for the s-protein which would prevent an initial interaction between the ACE2 protein and the s-protein of the virus.
Solomon wilson (April 3, 2020 9:43 AM)
I was researching the virus and came to a conclusion, that there may be a way to confuse the probes that the cell sends out for recon, because the probes are what determine if we are suitably ready to be a host, so I was wondering about tricking the virus so it can just kill itself off.
Riley Sorrell (April 4, 2020 2:53 AM)
Im not a researcher, but I read a lot and from my own health issues I learned about G6PD deficiency due to having that protein deficiency. Red blood cells hydrolysis when this deficiency is presence due to intake of foods or medications that are not chemically balanced with the body. Also, this deficiency fights off malaria which is almost identical to a person having pneumonia or flu like systems. By the red blood cells breaking down they create a type of protein that attacks the virus and makes a more oxygenated enriched blood which some viruses cannot last in. Im just curious to know out of the people whom survived this virus has any of these patients been tested for G6PD? From what I read it's 400 million people living with this deficiency and it can help fight off severe malaria. Maybe a vaccine can be formed from a person who has G6PD from extracting those proteins or hydrolysis red blood cells. If anyone has done research on G6PD deficiency please feel free to share your knowledge with me. Im thinking if the body developed a way to fight off malaria then it has to be a way the body can fight off the coronavirus. Volunteer testing may be essential during this pandemic so that a cure can be made.
dawn f rettew (July 11, 2020 1:20 AM)
Potassium may possibly be a solution?

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