Recently, Zhou Qiang Laboratory of West Lake University used cryoscope technology to successfully analyze the full-length structure of ACE2, the receptor of the new coronavirus. This is the first time in the world that the full-length structure of ACE2 has been parsed. The research content was launched on the pre-plated platform bioRxiv at around 3 a.m. Beijing time on February 19. This is also an important achievement of the emergency scientific research task of prevention and treatment of new coronavirus pneumonia in Zhejiang Province undertaken by West Lake University.
Frozen electron density map for ACE2-B0AT1 complexes
Previously, there have been studies to analyze the three-dimensional structure of a complex formed by ace2’s extracellular domain and SARS virus S protein. A team of researchers at the University of Texas at Austin recently demonstrated the S-protein structure of the new coronavirus. However, what state does ACE2 actually exist in the cell membrane? What are the similarities and differences between the new coronavirus and the combination of SARS virus and ACE2? Obtaining ace2’s full-length protein and its compound structure with the S protein will greatly help answer these questions.
ACE2-B0AT1 Complex Structure Map
Zhou Qiang’s laboratory has been tackling this problem. The first step is to get ace2 protein full-length protein, but ACE2 as a membrane protein itself is difficult to obtain in vitro stabilization. Zhou Qiang and postdoctoral student Yan Renhong found in the literature that ACE2 and an amino acid transport protein in the intestine, B0AT1, can form a complex. Based on their past research experience, the compound is likely to stabilize ACE2. Sure enough, they obtained ACE2 and B0AT1 high-quality stable compounds by co-expression, and successfully parsed their three-dimensional structure with a resolution of 2.9 E and a resolution of 2.7 E, which is critical for virus identification.
The ratio of the ACE2-B0AT1 complex to the previously parsed complex (the S protein of SARS-CoV and the compound of the PD domain of ACE2) is that the two compounds are anchored together through the PD domain.
By analyzing the full-length protein structure of ACE2, Zhou Qiang laboratory found that ACE2 exists in the form of a dipolymer, with both open and closed structural changes, but both of the conformations contain a mutual interface with coronaviruses.
This study lays the foundation for further analysis of the three-dimensional structure of the S-protein complex of full-length ACE2 and new coronaviruses. And this work itself provides many interesting clues to understanding the new coronavirus infestation of cells.
For example, can ace2’s dipolymers and the neo-coronavirus S protein have a higher level of crosslinking to facilitate the fusion or internal swallowing of the virus and host cell membranes? Previous studies have shown that ACE2’s extracellular region, if cut, will more effectively promote the infection of coronavirus, but the compound structure of ACE2 and B0AT1 shows that the presence of B0AT1 may prevent proteases from approaching this cutting site, does this explain whether the symptoms of viral infection mainly occur in the lungs without B0AT1?
This series of problems revealed through structural research is to be explored in multidisciplinary way in the future.
“Overall, the analysis of ace2’s full-length structure will help to understand the structural basis and functional characteristics of coronaviruses entering target cells and play an important role in the detection and optimization of inhibitors that block entry into cells,” said Professor Linxuan Zhang, director of the Center for Global Health and Infectious Diseases at Tsinghua University.
Zhou Qiang (right) and Yu Renhong (left)
The first author of this paper is Renhong Yu, a postdoctoral fellow at the School of Life Sciences at Westlake University, and Zhou Qiang, a researcher at the School of Life Sciences at West lake University. The first unit and the communication unit are both key laboratories for structural biology research in Zhejiang Province of West Lake University. This work has been the West Lake University frozen electric mirror platform and super-computing center support.
What is “structural biology”?
The so-called “seeing is true”, structural biology will constitute our body, supporting our life activities of biological macromolecules (proteins, nucleic acids) from a structural perspective revealed, to understand how they work, and how their abnormalities lead to lesions.
Research in this field can not only solve a series of major basic scientific problems in the field of life, but also help scientists to design drugs based on the special structure of disease-related molecules, and continuously improve the quality of human life.
In 2019, the key laboratory for structural biology research in Zhejiang Province was established, with Shi Yigong as the laboratory director.
(Originaltitle West Lake University successfully parsed the spatial structure of new coronavirus cell receptors)