Chinese scholars are awesome! The latest paper on the cover of Science: Revealing how the new coronavirus invades cells, produced by Westlake University

On March 27, an academic paper from a Chinese research team appeared on the cover of the world-renowned academic journal Science.

The research results of this paper are related to the new coronavirus. Specifically, the paper successfully analyzed the full-length three-dimensional structure of the new coronavirus (COVID-19) cell surface receptor ACE2, as well as the three-dimensional structure of the new coronavirus surface S protein receptor binding domain and the cell surface receptor ACE2 full-length protein complex.

It is worth mentioning that this paper is the first cover paper published in Science magazine specifically studying the new coronavirus since the global outbreak of the epidemic.

If you want to obtain the full text pdf of this paper, please reply to the keyword "327 paper" in the Leiphone.com WeChat public account (leiphone-sz) to extract it.

The pneumonia epidemic caused by the new coronavirus has brought obscure biological terms such as coronavirus, S protein, and ACE2 back into the public eye.

Researchers have found that the key to the novel coronavirus infecting human cells lies in the combination of the coronavirus's S protein and the human ACE2 protein. To be precise, the virus's S protein "hijacks" ACE2, which originally controls blood pressure, and invades the human body by combining with it.

So, what is S protein?

The full name of S protein is Spike Glycoprotein. It is located on the outermost layer of the novel coronavirus, like a protruding "crown".

According to the latest analysis results from the research team of the University of Texas at Austin, the S protein of the new coronavirus exists in the form of a trimer. Each monomer contains approximately 1,300 amino acids, of which more than 300 amino acids constitute the "receptor binding domain", which is where the S protein connects to ACE2.

So, what is ACE2?

ACE2, Angiotensin-converting enzyme 2, whose full Chinese name is angiotensin converting enzyme 2, is a protein involved in blood pressure regulation in the human body and is widely present in the lungs, heart, kidneys and intestines.

So, how does a protein in human cells come into contact with a virus?

Tao Liang, a distinguished researcher at West Lake University, used a vivid metaphor:

If you imagine the human body as a house and the new coronavirus as a robber, then ACE2 is the "door handle" of this house; the S protein grabs it, allowing the virus to penetrate deep into human cells.

Therefore, the study of S protein and ACE2 has become the key to understanding the process of the new coronavirus invading cells, which is also the research focus of Zhou Qiang's laboratory at Westlake University.

At the same time, as Sun Ren, distinguished professor of molecular and medical pharmacology and bioengineering at the University of California, Los Angeles, said:

The interaction between the S protein and its receptor is one of the important determinants of virus transmission. Therefore, observing the sequence of the S protein receptor binding domain and the changes in the corresponding structure during and after the cross-species transmission of the virus is an effective way for us to understand and confirm the transmission mechanism and predict the transmission ability.

The paper published on the cover of Science essentially explains the full picture of the virus S protein and ACE2 and their interaction with each other.

Structural basis for the recognition of the SARS-CoV-2 by full-length human ACE2

Based on the previously successful analysis of the high-resolution three-dimensional spatial structure of the full-length ACE2 protein, this paper has analyzed the complex structure of the full-length ACE2 protein and the receptor binding domain of the SARS-CoV-2 S protein, with an overall resolution of 2.9 angstroms (Note: Angstrom is a metric unit of length, 1 angstrom equals 0.1 nanometers, and this unit is named in memory of Swedish physicist Anders Jonas ngström), of which the resolution of the S protein receptor binding domain is 3.5 angstroms.

So, what did the researchers see from the resolved structure of the complex?

It turns out that in terms of morphology, the S protein of the new coronavirus is like a bridge across the surface of ACE2, and also like a hand of the virus, tightly grasping ACE2, which is very similar to the SARS virus. The receptor binding domain of the S protein of the new coronavirus is also very similar to the sequence of the SARS virus, with a similarity of 82%.

Further analysis allowed the researchers to see which amino acids on the surface of the novel coronavirus' S protein interacted with ACE2. Compared with the previously analyzed interaction between the SARS virus and ACE2, some of the amino acid residues in the novel coronavirus' S protein have undergone significant changes.

This may explain why the new coronavirus and SARS have different binding abilities to ACE2, which may affect the virus's infectiousness.

However, whether the virus's infectiousness has increased or decreased still needs to be verified through other experimental methods.

In fact, this research result was published on the preprint platform bioRxiv as early as February 21, Beijing time, and was made public to the whole society at the first time. On March 4, Eastern Time, the paper was officially accepted by Science magazine.

Finally, it appeared on the cover of the March 27 issue of Science magazine.

It is worth mentioning that the research team of Professor Wang Xinquan from Tsinghua University and the research team of Qi Jianxun from the Institute of Microbiology, Chinese Academy of Sciences independently analyzed the crystal structures of the N-terminal protease domain of ACE2 and the receptor binding domain of the SARS-CoV-2 S protein.

This information supports and complements the related electron microscopy structures obtained by Zhou Qiang's team.

As the COVID-19 pandemic continues to spread across the globe, scientific research related to the virus has attracted much attention - so what does this research result, which has been fully recognized by Science magazine, mean?

Zhou Qiang’s team also gave specific explanations on this.

Zhou Qiang's team said that the analysis of the structure of the complex is a breakthrough in the field of basic research and has no necessary connection with the development of anti-epidemic drugs.

However, on the other hand, it is indeed very important. Because the structure of a protein largely determines its properties and functions, seeing the structure of the new coronavirus S protein, ACE2 and their interactions is equivalent to seeing the "enemy's appearance", providing more information for subsequent scientists' targeted drug research.

Based on this study, computational biology researchers can build different models and conduct targeted research to determine what kind of mutations may further enhance the interaction between S protein and ACE2, thereby designing drugs and antibodies targeting S protein or ACE2 protein; or designing small molecules to disrupt the interaction between them.

All of these can provide a solid foundation for drug design and development of testing methods.

Leifeng.com noted that this research has also been recognized by many experts in the discipline. For example, Michael K. Rosen, director of the Department of Biophysics at the University of Texas Southwestern Medical Center and researcher at the Howard Hughes Medical Institute, believes that:

This biophysical research by Zhou Qiang's team has made important progress in understanding how the new coronavirus infects human cells. The relevant research results will ultimately play a key role in the development of accurate diagnosis and treatment methods for new coronary pneumonia.

Sun Ren, distinguished professor of molecular and medical pharmacology and bioengineering at the University of California, Los Angeles, also said:

The research of Zhou Qiang's team has taken an important step in understanding the mechanism of virus invasion of cells, and will help us further understand the transmission of viruses across species and between species. Comparative studies on the interaction modes of the S proteins of different coronaviruses and ACE2 of different hosts may provide more key information.

This paper result comes from Zhou Qiang's laboratory at Westlake University.

Among them, Zhou Qiang, a researcher at the School of Life Sciences of Westlake University, is the corresponding author, and Yan Renhong, a postdoctoral fellow at the School of Life Sciences of Westlake University, is the first author.

Zhou Qiang, born in 1982, graduated with a bachelor's, master's and doctoral degree from Tsinghua University. After graduating with a doctorate, he continued to stay in the laboratory to conduct postdoctoral research. After completing his postdoctoral research in 2015, he served as an associate researcher in the research group of Professor Yan Ning of the School of Medicine of Tsinghua University. In early 2019, he joined Westlake University as a Westlake Scholar and Distinguished Researcher to carry out independent research.

In the research field, Dr. Zhou Qiang has been engaged in the study and research of cryo-electron microscopy single-particle technology for a long time. In collaboration with colleagues and collaborators, he has analyzed the structures of many important biological macromolecular complexes or membrane proteins. His main work includes SNAP-SNARE complex, inflammasome complex, Niemann-Pick C1 (NPC1) protein, eukaryotic voltage-gated sodium channel, etc.

Among them, the resolution of the eukaryotic voltage-gated sodium ion channel combined with the gating regulatory toxin Dc1a and tetrodotoxin reached 2.6 angstroms, which is the highest resolution of membrane protein structures analyzed by cryo-electron microscopy single-particle technology published so far, laying the foundation for the subsequent structure-based small molecule drug development.

Researcher Zhou Qiang's doctoral research group mainly uses cryo-electron microscopy as the main research method, combining biochemistry, molecular biology, computational biology and other technologies to study the structure and working mechanism of biological macromolecular complexes and membrane proteins related to major diseases or important biological processes.

Leifeng.com learned that in the past two years, Zhou Qiang's laboratory has been studying human amino acid transporters. They have locked in several target proteins, ACE2 is one of them; then the COVID-19 outbreak occurred, Zhou Qiang's team quickly increased the priority of ACE2 research and finally achieved today's research results.

Congratulations to Zhou Qiang's team!

Reference links for this article:

https://www.westlake.edu.cn/info/1017/4362.htm

https://www.westlake.edu.cn/info/1622/3832.htm

https://science.sciencemag.org/content/367/6485/1444

https://science.sciencemag.org/content/367/6485