LONDON – Two papers published online in Nature following accelerated peer review provide fine detail of how the spike protein on the COVID-19 coronavirus binds to the angiotensin converting enzyme 2 (ACE2) through which it infects its human host.

The two studies, which were posted on March 30, 2020, provide important insights into the interaction of the virus and its receptor, showing there are huge similarities with how the related sudden acute respiratory syndrome (SARS) virus binds to ACE2, but also highlighting significant differences.

The atomic level 3D structural data will inform vaccine design and provides a precise target for the discovery of antibodies that bind preferentially to the receptor.

“These two papers, one from China and one from the U.S. are a vivid demonstration of the role structural biology will play in defeating the pandemic,” said Jim Naismith, professor of structural biology at Oxford University and director of the Rosalind Franklin Institute, a research lab dedicated to applying protein structure data to drug discovery.

An X-ray crystallography study by researchers at Tsinghua University, Beijing, confirms that while the way in which the COVID-19 virus binds to ACE2 is nearly identical to how the SARS virus binds, there are a few key amino acid differences. Those explain why two antibodies that are effective against SARS could not neutralize the COVID-19 virus, SARS-CoV-2, the researchers say.

In the second paper, researchers at the University of Minnesota show that, compared to SARS, the receptor binding domain in the COVID-19 virus has a more compact conformation. At the same time, several amino acid changes stabilize two virus binding hotspots at the interface between the binding domain and ACE2. Those structural features enhance the binding affinity between the virus and the host cell receptor.

The structural information lays out all the functionally important epitopes, while the receptor binding domain itself could function as a subunit vaccine. That could be helpful in increasing the efficacy of subunit vaccines and in providing a blueprint for antibody drugs that preferentially bind to the ACE2 receptor, said Fang Li, associate professor in the Department of Veterinary and Biomedical Science at the University of Minnesota, an author of the paper.

“With the structure in hand, the study has mapped out the important binding sites on SARS-CoV-2 for antibody drugs to act on,” Li told BioWorld. “Those sites are also valuable for vaccine design, as vaccines containing [them] can induce the production of antibodies in humans,” he said.

Naismith agreed the two papers are “a very important step in understanding why COVID-19 is so dangerous” and will help to shape drug and vaccine design. “What is most interesting are the very subtle differences between COVID-19 and SARS in how the atoms [of the viral spike] protein/ACE2 complex are arranged. These very subtle differences are why COVID-19 virus binds to the receptor more tightly.”

The findings of Li and his team draw on a decade of structural studies of the SARS virus. His group predicted that, as with SARs, the novel coronavirus causing COVID-19 infections also uses ACE2 as its receptor, a suggestion that has been confirmed by other studies.

The data derived previously from the crystal structure of the SARS spike protein binding to ACE2 acted as a template for the COVID-19 research.

That highlighted the structural differences in the binding domain of the COVID-19 virus which allow it to become more compact and form a better contact with ACE2. In addition, COVID-19 virus has evolved strategies to stabilize the two hotspots on ACE2 that are critical for coronaviruses to bind.

The structural similarity in ACE2 binding to SARS and COVID-19 viruses suggests a very close evolutionary relationship. But taken overall, the data confirm COVID-19 virus has a significantly higher ACE2 binding affinity than the SARS virus.

Li’s group also used the crystal structure data to investigate how COVID-19 was transmitted from bats to humans. They found the closely related RaTG13 bat coronavirus also uses ACE2 as its receptor, suggesting it could infect humans directly.

They also found similar motifs in the binding domain, indicating the COVID-19 virus may have evolved from RaTG13, or a related bat coronavirus. Because RaTG13 binds to ACE2, it is possible there is no intermediate host between bats and humans. However, it also has been suggested pangolins acted as intermediates.

“Both scenarios are possible,” said Li. “Our study shows that the evolution of bat RaTG13 can potentially lead to the emergence of SARS-CoV-2. But there could be multiple evolutionary routes that the virus has taken to turn into its current form,” he said.

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