In a new study published today in Science, researchers from the University of Texas and NIH in the United States are using cryoscopes for the first time to demonstrate the molecular structure of the new coronavirus protrusion protein. The study was published on February 16th on the preprinted website bioRxiv and was quickly published in the journal Science through peer review. The study identified and presented three key points:
Frozen electro-mirror image of the new coronavirus protrusion protein
Reconfirming the protrusion protein structure of coronavirus is a key area for vaccine response;
2019-nCoV’s prosthesis of protoscocin protein and cell ACE2 receptor is higher than SARS-CoV;
Multi-clone antibodies specific to SARS-CoV protoprotein receptor binding domain (RBD) cannot be combined with 2019-nCoV, and antibodies of both viruses are restrictive.
Including the Chinese Academy of Sciences Shanghai Pasteur Institute, such as the use of genetic sequence modeling, Shi Zhengli team in nature published in the cell level experiments, there have been a number of studies from different angles confirmed that, like SARS-CoV, 2019- nCoV also infects human cells using the action of protrusion proteins and ACE2 receptors.
S Protein can be divided into two functional units according to protein structure function: S1 and S2 protein subunits. S1 promotes the ability of viruses to bind to host cell receptors, which contain an important C-end receptor binding domain (receptor-binding domain, RBD), which is responsible for binding to the receptor.
In the previous computer model analysis, the new coronavirus and SARS protogenic protein were less homologous, and the amino acid sequence of the two virus protosins was only 76.47%. However, some gene regions in the RBD domain of the two viruses have high homologousness with SARS. Of the five key sites of SARS infection, one was retained by the new coronavirus, and the remaining four had amino acid substitution and variation.
Four of the five key amino acids in the new coronavirus protrusion protein were bound with the ACE2 protein, but it maintained the original structure of the SARS virus protrusion protein and ace2 protein. This suggests that the new coronavirus is still virally infected and transmitted through the same receptors and mechanisms as SARS.
New studies published in Science suggest that the new coronavirus uses a highly glycogenitose homologous tripolymer protrusion protein to enter host cells. During this viral fusion (fusion), the protoprotein undergoes structural changes, including the s1 subunit of the virus binding to the host cell receptor, causing the protoprotein triol to become unstable, which in turn causes the S1 subunit to fall off, and the S2 subunit to form a highly stable post-fusion structure.
Through structural analysis, it is found that RBD in S1 sub-bases experiences hinged motion, which is very similar to SARS-CoV and MERS-CoV. Through this movement, the protrusion protein can temporarily hide or expose the key sites of receptor binding. These two states are called “down” and “upper” conformations, wherein, the “lower” conformation corresponds to the receptor non-binding state, the “up” conformation corresponding receptor binding state, the receptor binding state is more unstable, so it is the perfect site for the vaccine.
Based on the experience of acquiring protoproteins in SARS-CoV and the published new coronavirus sequence, the researchers obtained pre-fusion profusion proteins for 2019-nCoV in laboratory cells and demonstrated their 3.5-definition HD structure diagrams using a frozen electric mirror after purification.
The study also showed a dynamic map of S1 sub-based hinged motion, which is very close to beta-coronaviruses such as SARS-CoV and MERS-CoV, and even to some of the more distant alpha-coronaviruses. The findings prove that the infection mechanism of the new coronavirus is consistent with the characteristics of other coronaviruses.
S1 sub-range motion observed from top and side, respectively
In addition, studies indicate that 2019-nCoV and bat coronavirus RaTG13 have 98% similarity in the S protein sequence. Amino acid residue variation appeared at s1/S2 sub-base connections, and 17 of the 29 residual variants appeared in the RBD region. The study compared 61 available protoprotein sequences with existing databases, and found that only 9 amino acid substitutes could be compared to 2019-nCoV, but the amino acid substitutes in these 9 were conservative and had very limited effect on changing the structure and function of the new coronavirus protrusion protein.
Since ACE2 is a binding part of the protoprotein, the study compared the affinity between 2019-nCoV and SARS-CoV protosins and ACE2. The results show that the affinity between 2019-nCoV and ACE2 is 10 to 20 times that of SARS-CoV. And the author created the structure of ACE2 and the protrusion protein binding graph, frozen electric mirror, its binding form is highly similar to SARS-CoV. Studies have shown that the high affinity of the neo-coronavirus protogenic protein with ACE2 is likely to help it produce a high degree of human-to-human infectiousness.
The study finally tested three so-published polyclonal antibodies against the SARS-CoV RBD region, but although the two viruses have a high homologous nature, these three polyclonal antibodies, which are closely bound to the SARS-CoV RBD region, have no binding force in the new coronavirus. The results suggest that antibodies in the SARS-CoV study may not have any effect on 2019-nCoV and need to be redesigned for the specificity of the new coronavirus.
However, in the case of the publication of the frozen electro-mirror map, it is possible to make a “probe” based on the structure of the new coronavirus protrusion protein and specifically isolate the effective antibody from the recovering person’s blood to make a vaccine.