Understanding how a virus enters a host cell and the details surrounding how it binds to the receptor on the host cell is critical to facilitate the development of detection methods, antiviral therapeutics, and vaccines. Once this critical piece of information is solved, it can be utilized to target and combat the virus.

Researchers have been working at breakneck speed to understand this puzzle piece for the SARS-CoV-2 virus, at the heart of the global epidemic of COVID-19. Now, a team of scientists from China reports the cryo-EM structure of the full-length human angiotensin-converting enzyme 2 (ACE2) protein—the point of entry for the SARS-CoV-2 virus into human cells.

The work is published in Science in a paper titled, “Structural basis for the recognition of the SARS-CoV-2 by full-length human ACE2.

ACE2 is the cellular receptor for both SARS coronavirus (SARS-CoV) and SARS-CoV-2.

In late February, researchers determined the first 3D atomic-scale map of the spike glycoprotein of the novel coronavirus (SARS-CoV-2). Also mapped by cryo-EM, this finding, published in the Science article, “Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation,” marked an important step forward in understanding the virus’s entry into host cells.

The authors of the February paper determined a 3.5 Å-resolution cryo-EM structure of the spike trimer. The predominant state of the trimer, the authors wrote, “has one of the three receptor-binding domains (RBDs) rotated up in a receptor-accessible conformation.” They also showed “biophysical and structural evidence that the 2019-nCoV S binds [angiotensin-converting enzyme 2] ACE2 with higher affinity than SARS-CoV S.”

Now, not even one month later, Qiang Zhou, PhD, from Westlake University in Zhejiang Province, China, presented cryo-EM structures of full-length human ACE2, in the presence of a neutral amino acid transporter B0AT1, with or without the RBD of the surface spike glycoprotein of SARS-CoV-2. The structures are at an overall resolution of 2.9 Å, with a local resolution of 3.5 Å at the ACE2-RBD interface.

The RBD domains of SARS-CoV and SARS-CoV-2 are similar, the study found. However, some distinctions were found when they were in their interfaces with ACE2. The team compared the binding of the RBD domain of SARS-CoV-2 versus the RBD domain of SARS-CoV to ACE. Comparing these interactions could lead to insights into the strength or weaknesses of those interactions and suggest differences in the viruses host cell binding— information that may inform a broader comparison of the two viruses.

“Our findings not only shed light on the mechanistic understanding of viral infection,” say the authors, “but will also facilitate development of viral detection techniques and potential antiviral therapeutics.”

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