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Biochemistry ChemVsCOVID Coronavirus

#ChemVsCOVID: How was the spike protein structure identified?

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The second part of the #ChemVsCOVID series, produced with the Royal Society of Chemistry, looks at how the structure of the spike protein was determined and how it helped our efforts against the virus.

The SARS-CoV-2 virus has 26 proteins. This is a really tiny number; to put it into context, it’s estimated that the human body may contain as many as 400,000 proteins. From this limited number of proteins, one has received more attention than the rest over the past year: the spike protein.

The virus’s spike protein is the key that allows it to gain entry to our cells. It binds to an enzyme, ACE2, found in cell membranes in parts of our bodies, including most organs.

The spike protein has two regions, S1 and S2 for short. S1 is the top of the protein, the part which binds to the ACE2 enzyme. This binding triggers a change in the shape of the spike protein. S2 is the lower part of the protein which then fuses with the human cell membrane. This is what allows the virus to enter our cells.

What we call the spike protein is actually a ‘trimer’ built up from three individual proteins. There are approximately 26 of these spike protein trimers per virus particle. Each trimer is studded with sugar molecules called glycans, which act as a sort of molecular camouflage, hiding the spike protein from our immune system.

Scientists know all of this detail about the spike protein largely as a result of using cryo-electron microscopy. This technique won the Nobel Prize in Chemistry in 2017, and involves firing electrons at a frozen target to determine its structure.

To do this, samples of the protein are rapidly frozen at very low temperatures. This rapid freezing prevents ice crystals from forming, allowing proteins to be frozen and observed in their usual shapes and structures.

An electron microscope then fires a beam of electrons at the sample repeatedly, producing a number of two-dimensional images from different angles. By combining these two-dimensional images, we can build up a three-dimensional picture of the protein.

Knowing the structure of the spike protein has been particularly useful in the fight against the virus. Firstly, it has hastened the development of vaccines, many of which are based around the spike protein. In particular, the Novovax vaccine which may soon receive approval for use is based on nanoparticles made up of stabilised spike proteins.

Secondly, knowing the structure of the spike protein has helped us understand how it acts in our body: both how it helps the virus infiltrate our cells, and how potential medicines to combat the virus might affect it. It also helps us understand how our own antibodies try to neutralise the virus, as it is also the spike protein that they target

Finally, it allows us to understand how genetic mutations might affect the virus. Some of these mutations can introduce changes to the spike protein structure, so being able to compare structures between different variants of the virus helps us understand how these changes might affect it.

This graphic was developed in partnership with the Royal Society of Chemistry. See the full #ChemVsCOVID series of graphics here.

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