Researchers have determined the first 3D atomic-scale map of the spike glycoprotein of the novel coronavirus (SARS-CoV-2). Mapped by Cryo-EM, this finding from teams at the University of Texas (UT) at Austin and the National Institutes of Health is an essential step to allow researchers to develop vaccines and antiviral drugs to combat the virus.
The work is published in the Science article, “Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation.”
The authors determined a 3.5 Å-resolution cryo-EM structure of the S trimer. The predominant state of the trimer, the authors write, “has one of the three receptor-binding domains (RBDs) rotated up in a receptor-accessible conformation.” They also show “biophysical and structural evidence that the 2019-nCoV S binds [angiotensin-converting enzyme 2] ACE2 with higher affinity than SARS-CoV S.”
Jason McLellan, PhD, associate professor at UT Austin, and his colleagues have spent many years studying other coronaviruses, including SARS-CoV and MERS-CoV. They had already developed methods for locking coronavirus spike proteins into a shape that made them easier to analyze and could effectively turn them into candidates for vaccines. This experience gave them an advantage over other research teams studying the novel virus.
“As soon as we knew this was a coronavirus, we felt we had to jump at it,” McLellan said, “because we could be one of the first ones to get this structure. We knew exactly what mutations to put into this, because we’ve already shown these mutations work for a bunch of other coronaviruses.”
Just two weeks after receiving the genome sequence of the virus from Chinese researchers, the team had designed and produced samples of their stabilized spike protein. It took about 12 more days to reconstruct the 3D atomic-scale map of the spike protein and submit a manuscript to Science, which expedited its peer review process.
The molecule the team produced, and for which they obtained a structure, represents only the extracellular portion of the spike protein, but it is enough to elicit an immune response in people, and thus serve as a vaccine.
Additionally, the team tested several published SARS-CoV RBD-specific monoclonal antibodies and found that they do not have appreciable binding to the SARS-CoV-2 S protein, suggesting antibody cross-reactivity may be limited between the two RBDs.
Next, McLellan’s team plans to use their molecule to pursue another line of attack against the virus that causes COVID-19, using the molecule as a “probe” to isolate naturally produced antibodies from patients who have been infected with the novel coronavirus and successfully recovered. In large enough quantities, these antibodies could help treat a coronavirus infection soon after exposure. For example, the antibodies could protect soldiers or health care workers sent into an area with high infection rates on too short notice for the immunity from a vaccine to take effect.
