This model shows the structure of the ear protein in its closed configuration, in the original D614 form (left) and the mutant form (G614). In the mutated vein protein, the 630 loop (in red) stabilizes the vein so that it cannot open prematurely and the SARS-CoV-2 becomes more contagious. Credit: Bing Chen, PhD, Boston Children’s Hospital
Cryo-EM study shows how structural changes in G614 variants stabilize the peak.
The rapidly spreading coronavirus variants from the United Kingdom, South Africa and Brazil raise concerns and questions about whether COVID-19 vaccines will be protected against it. New work led by Bing Chen, PhD, at Boston Children’s Hospital, analyzed how the structure of the coronavirus proteins changes with the D614G mutation – carried by all three variants – and showed why these variants can spread faster. The team has its findings in Science on March 16, 2021.
Chen’s team took down the nails with cryo-electron microscopy (cryo-EM), which has up to atomic level resolution. They found that the D614G mutation (replacement by a single amino acid “Letter” in the genetic code for the vein protein) makes the vein more stable compared to the original EARS-CoV-2 virus. As a result, more functional nails are available to bind to the cells’ ACE2 receptors, making the virus more contagious.
The prevention of deformation of nails
In the original coronavirus, the vein proteins would bind to the ACE2 receptor and then dramatically change shape and fold on themselves. This enabled the virus to fuse and enter its membrane with our own cell membranes. However, as Chen and colleagues reported in July 2020, the nails would prematurely change shape and fall apart before the virus could bind to cells. While it slows down the virus, the shape change has also made it harder for our immune system to contain the virus.
“Because the original ear protein would dissociate, it was not good enough to elicit a strong neutralizing antibody response,” says Chen.
When Chen and colleagues imaged the mutant vein protein, they found that the D614G mutation stabilizes the vein by blocking the premature deformation. Interestingly, the mutation also causes the nails to bind more weakly to the ACE receptor, but the fact that the spikes are less likely to fall apart prematurely generally makes the virus more contagious.
“Say the original virus has 100 nails,” Chen explains. ‘Due to the instability of the mold, you can only function 50 percent of it. In the G614 variants, you may have 90 percent that is functional, so although it does not bind as well, the chances are that you will be infected. “
Chen suggests that redesigned vaccines contain the code for this mutant ear protein. The more stable form of the peak should make any peak-based vaccine (like the Moderna, Pfizer, and Johnson & Johnson vaccines) more likely to cause protective neutralizing antibodies.
Future direction: A medicine to block coronavirus access
Chen and his colleagues are applying structural biology to better understand how SARS-CoV-2 binds to the ACE2 receptor, with a view to therapeutic agents to prevent the virus from accessing our cells.
In January, the team at Nature Structural & Molecular Biology showed that a structure-designed “lure” ACE2 protein binds the virus 200 times stronger than the body’s own ACE2. The lure has strongly inhibited the virus in cell culture, suggesting that it may be an anti-COVID-19 treatment. Chen now plans to advance this research into animal models.
Chen is senior researcher on the page in Science. Jun Zhang and Yongfei Cai in Boston Children’s Department of Molecular Medicine were co-authors. Co-authors were Tianshu Xiao, Hanqin Peng, Sophia Rits-Volloch and Piotr Sliz of Boston Children; Jianming Lu of Codex BioSolutions, Inc., Sarah Sterling and Richard Walsh Jr. of the Harvard Cryo-EM Center for Structural Biology (Harvard Medical School); and Haisun Zhu, Alec Woosley, and Wei Yang of the Harvard Institutes of Medicine. The work was funded by the National Institutes of Health (AI147884, AI147884-01A1S1, AI141002, AI127193), a COVID-19 grant by MassCPR and Emergent Ventures.