Renhong Yan et al. / Science, 2020
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Chinese researchers have determined the crystal structure of the molecule that SARS-CoV-2 binds to when it enters the cell, according to Science. This molecule is an angiotensin-converting enzyme 2. The results will accelerate the development of effective anti-coronavirus agents.
To enter the cell, SARS-CoV-2, like other coronaviruses, uses a spike protein (spike, S-protein). By it, it attaches to a target on the surface of the host cell. Genome sequencing of the new coronavirus showed that in his case the target is angiotensin-converting enzyme 2 (ACE2). The SARS-CoV virus, one of the closest relatives of the new coronavirus, binds to the same molecule.
This enzyme cleaves one amino acid from type II angiotensin and thereby changes its properties: the resulting molecule has a vasoconstrictor effect and can play a role in acute respiratory distress syndrome. Another function of ACE2 is to modulate the transfer of amino acids across the cell membrane. Its enzyme implements, supporting the desired form of the membrane conveyor of amino acids B0AT1.
Structural biologists from the University of Westlake in Hangzhou under the supervision of Qiang Zhou using cryoelectronic microscopy (freezing individual molecules so that they form crystals and “scanning” them with an electron microscope) obtained data on the structure of ACE2 in the presence of B0AT1. The molecules were in one of two states: associated with a fragment of the coronavirus spike protein and without any connection with it. The resolution of the models was 2.9 Å (angstrom). Particular attention was paid to the site by which the spike binds to angiotensin-converting enzyme 2.
–A complex of two ACE2 molecules (ACE2, blue and blue), two amino acid transporters (B0AT1; pink) and two fragments of the viral protein “thorn” (RBD, yellow) and its location in the cell membrane
Renhong Yan et al. / Science, 2020
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– It turned out that ACE2 and B0AT1 form a heterodimer – a molecule of two different parts. Two such molecules, in turn, form a homodimer. Its integrity is ensured by the interaction of the same sections of two molecules of the angiotensin-converting enzyme. The “thorn” SARS-CoV-2, due to polar interactions, attaches to ACE in the region of the site with protease activity (protease domain) – one that provides the separation of one amino acid from type II angiotensin. Moreover, a trimer (a complex of three) of viral proteins can be associated with one ACE2, and two trimers, respectively, with the described dimer.
Although the researchers did not get a complete decoding of the structure of ACE2, their work answered key questions: which amino acids can be replaced in a fragment of angiotensin-converting enzyme 2, which binds to SARS-CoV-2 S-protein to reduce the likelihood of their combination – and with it and cell infection. For example, if you replace 426 amino acid arginine with a different amino acid, and with it asparagine in position 439, they will not be able to form a bridge with each other, and the chances of the virus attaching will decrease.
Knowing all this, one can selectively select those molecules that are able to bind with the greatest efficiency either to the ACE2 protease domain or to the coronavirus S-protein and prevent these two substances from binding. This, the authors expect, will accelerate the creation of drugs against SARS-CoV-2.
More recently, another group of researchers from China showed that there are at least two varieties of SARS-CoV-2 – the older “S” type, infection of which usually leads to milder forms of COVID-19, and a more “young” and hard to tolerate L- a type.
Svetlana Yastrebova
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