Zhang Boli, Shi Yigong and Li Lanjuan all like this
How many cows are the complete structure of the new crown virus?
Our reporter Zhang Jiaxing
The complete structure of the new coronavirus
"I hope you can take a good look. Thinking about the evolution of the new crown virus, it really gives people a lot of enlightenment." On September 19, at an academic seminar, the national honorary title of "People's Hero", academician of the Chinese Academy of Engineering Zhang Boli showed a complete structure diagram of the new coronavirus.
What picture is this?
It was actually able to win Academician Zhang Boli to call CALL for it.
More than that, according to reports, the research has been strongly supported by Shi Yigong, an academician of the Chinese Academy of Sciences, and Li Lanjuan, an academician of the Chinese Academy of Engineering, and has been strongly urged by Princeton University professor Yan Ning "don’t make excuses and must finish writing the paper in 3 days." .
On September 20, a reporter from Science and Technology Daily went to the research group of Li Sai, a researcher at the Advanced Innovation Center for Structural Biology, Tsinghua University, to try to find out.
Do "CT" for the entire virus to see clearly from the inside out
On September 15, "Cell" published a research paper "Molecular Structure of New Coronavirus" completed by Li Sai's team and Academician Li Lanjuan's team. They used cryo-electron microscopy tomography to see the new coronavirus clearly.
Cryo-electron microscopy, structural analysis, hearing these two key words, technology fans may think: it has been popular for many years, what new things can there be, is it just to change the material and do it again?
However, the development of new technology can always make people call "infertility of knowledge limits imagination!"
"We put the new crown virus under a cryo-electron microscope and took a picture every 3° rotation. A total of 41 pictures were taken, and then stereo reconstruction was carried out." Li Sai told a reporter from Science and Technology Daily that each rotation must be at the same height as the previous one. It is difficult to achieve high accuracy even with slight lateral deviation.
This distribution shooting method is similar to the medical CT imaging principle, the difference is that the former uses electron diffraction imaging, while the latter uses X-ray diffraction imaging.
As the saying goes, "knowing people, knowing the face and not knowing the heart".
Li Sai insisted on analyzing the "heart" of the virus.
The team "strikes a flashlight" inside the virus, penetrates the envelope, directly hits the inner RNA and entanglement structure, showing the most complete image of the new coronavirus so far.
Analyze 100TB data to draw the "popular face" of the new crown virus
In 2018, Li Sai, who originally worked at Oxford University in the UK, returned to China to work at Tsinghua University and set up his own laboratory.
Prior to this, Li Sai had seen and analyzed more potent level 4 viruses, and also allowed multiple level 3 viruses to appear in real life, including the frightening Sara virus and Rift Valley fever virus.
When the new crown virus hit, Li Sai could not sit still.
Through Shi Yigong, he contacted Li Lanjuan, who was on the front line of the epidemic in Wuhan, hoping to obtain the inactivated new crown virus for power microscope research.
Academician Li Lanjuan immediately arranged the team to dock with Li Sai.
Through strict paraformaldehyde inactivation, although the new coronavirus is "dead", it can still remain alive.
Subsequently, the inactivated virus entered the laboratory of Tsinghua University through strict procedures.
After getting the virus strain, Li Saihe's team worked more than 120 hours per week.
In April, the team successfully collected two batches of 100TB high-quality cryo-EM tomographic image data.
What are the core characteristics of a virus with a thousand poisonous faces?
When the research enters the stage of calculation and analysis, that is, when the sub-tomographic image averaging method is used to obtain a high-resolution structure, the virus must be reconstructed and the core features must be assembled to draw the new crown virus "popular face".
Which spike protein is the most representative among the 3D conformations of 2300 viruses?
Li Saihe’s team began manual selection. This is a work with a very "artisan" characteristic. Based on the researchers' past experience in other virus research, 50,000 spike proteins on the surface of the virus were selected to enter the next step. Protein analysis.
After a comprehensive and partial analysis, the "cunning" nature of the new coronavirus is undoubtedly revealed-the surface spike protein is very small, with an average of less than 30, but it can freely roam and rotate.
"In the scope of human cognition, it is the first time we have seen such an enveloped virus." Li Sai said that the characteristic of protein rotation allows the new coronavirus to freely adjust its position and bind to the receptor when it attacks cells.
The characteristic of "seeing the wind and turning the rudder" makes it extremely contagious.
The strategy of locking the skeleton protein to crack the virus attacking the host
Genetic material determines the traits of living organisms. Coronavirus has the longest RNA among all RNA viruses currently known, with nearly 30,000 nucleotides. How did it do it?
The Li Sai team set their sights on the backbone protein that houses RNA.
"These areas have not been studied before." Li Sai said that when reshaping the ribonucleoprotein complex (RNP), there are no possible expectations or references.
He led his students to "treasure hunt" among 20,000 ribonucleoproteins.
"Most of them need to be selected by me personally, because we have too little knowledge of internal proteins, and these proteins are crowded together like a bunch of grapes in the virus body, and must be distinguished with high precision, so as not to mistake the parts of other proteins. Come in the circle." Li Sai said.
The protein group in the envelope of the new coronavirus is becoming clearer, showing a "egg in a nest" structure.
In the "old nest" of the new coronavirus, the ultra-long RNA is densely entangled, and the protein provides the RNA with a super-regular skeleton. They are arranged in a hexamer "bird's nest" pattern against the envelope, and they are arranged on four sides at the center of the sphere. The "pyramid" arrangement of the body.
In this way, the new coronavirus can not only squeeze the nucleic acid 100 times the body length into its own body, but also meet the unpredictable external challenges.
"The regular arrangement of nucleoproteins helps to receive ultra-long RNA; when the virus attacks the host, it can release the RNA in an orderly manner without any defects." Li Sai said that they can evolve into a host when they attack the host. Rotating spools output at high speed and infect new hosts.
Global sharing of structural data helps develop more efficient vaccines
Humans know very little about the new coronavirus.
Because of this, academia often has different answers to the same question.
For example, regarding the ability of a neutralizing antibody named CR3022 to inhibit the new coronavirus, in March, "Science" published an article that it has a strong neutralizing ability; but other teams later found that CR3022 lacks in live viruses And effect.
Why are the research results contradictory?
It turns out that the former neutralization test used recombined viral proteins in vitro, while the latter used live viruses.
"The high-precision complete structure diagram of the new coronavirus shows that its surface protein will change its face: sometimes it is exposed to the antigen, sometimes it is hidden, and sometimes it is in a state of fusion with the membrane. In vitro recombination can only imitate its changing face. 'To reveal the law of its action." Li Sai said.
The research of Li Sai's team has also corrected and supplemented the previous research.
For example, in the first cryo-EM photo of the new coronavirus released in March this year, the spike protein of the virus is almost all needle-shaped.
"This may be due to the inactivation of the live virus destroying the protein structure of the virus itself, causing the S1 subunit to fall off, and the S2 subunit undergoes a conformational change to the state of fusion with the membrane." Li Sai said.
The high-precision complete structure diagram of the virus will help humans develop more efficient vaccines.
"The current inactivation method of inactivated vaccines may not be able to leave a'whole corpse' on the spike protein of the virus, which theoretically will affect its effectiveness in stimulating neutralizing antibodies." Li Sai said, these can be improved In-depth research work.
The Li Sai team has uploaded the high-definition three-dimensional structure of the new crown virus to the structural biology database EMDB (Electron Microscopy Data Bank) for free download by scientists around the world, helping popular science education, scientific research, and vaccine development.