COVID-19: Understanding the Viral Gatekeeper and its Evolving Variants

Image of covid-19 spiked artwork painted in green

The COVID-19 pandemic has been a defining moment in our history, not just for its devastating health consequences but also for the scientific breakthroughs it has spurred. At the heart of this intricate puzzle lies the viral spike protein, a crown-like structure adorning the surface of the SARS-CoV-2 virus. This seemingly simple protein holds the key to understanding the virus's invasion strategies and, ultimately, developing effective countermeasures.

The Shape-Shifting Spike

Imagine a microscopic lockpicker, gracefully transitioning from a dormant state to one primed to crack the code of a human cell. This is the story of the viral spike protein, the crown-like adornment on the surface of the SARS-CoV-2 virus. This seemingly simple structure holds the key to understanding the virus's intricate invasion strategy and, ultimately, developing effective countermeasures.

Unlike a static lockpick, the spike protein is a master of disguise. It can switch between two distinct conformations, a receptor-inaccessible (closed) state and a receptor-accessible (open) state, based on the positions of its receptor-binding domains (RBDs). These RBDs act like prongs, searching for a specific partner – the angiotensin-converting enzyme 2 (ACE2) receptor on human cells.

Dissecting the crown

A Two-Part Masterpiece: To truly understand the spike protein's vulnerabilities, scientists have delved into its intricate structure. Imagine the protein as a two-part crown:

  • The Bottom Ring: The S1 subunit holds the RBDs, the key that unlocks the ACE2 receptor.
  • The Middle Ring: The S2 subunit facilitates membrane fusion, acting as the hinge that allows the virus to merge with the host cell.
Open and close states of SARS-CoV-2 spike

 

In the closed state, the RBDs are tucked away, hidden within the protein's folds. This cloaked form allows the virus to evade detection by our immune system. But when the right conditions arise, the spike protein undergoes a dramatic transformation. Like a flower blooming, the RBDs unfurl, extending outwards and becoming primed for engagement with ACE2 receptors.

This dynamic process has been captured in stunning detail by powerful scientific techniques like X-ray crystallography and cryo-electron microscopy. These technologies allow scientists to peer into the intricate world of atoms and molecules, revealing the precise structural mechanism of viral invasion.

 

SARS-CoV-2 S-ACE2 complex (PDB ID: 7DF4)

By visualising the precise shapes and interactions of the spike protein and ACE2 receptor, researchers have gained invaluable insights into how the virus gains entry into our cells. This knowledge has been instrumental in the development of vaccines, which target the RBDs and prevent them from binding to ACE2, effectively thwarting the virus's invasion strategy.

Variant structures

The spike protein is not static; it constantly evolves through mutations, generating variants with altered properties. Some mutations, like the infamous N501Y, enhance binding affinity to ACE2, leading to increased transmissibility. Others, like E484K, act like a shield, evading the immune response generated by vaccines or previous infection. Whereas D614G increases its propensity to adopt the open conformation that is competent to bind the receptor. These mutations, depicted as subtle alterations in the artwork's intricate crown, can have profound consequences, influencing the severity of disease, the efficacy of vaccines, and the global spread of the virus.

These mutations give rise to variants like Alpha, Delta, and Omicron, each with its own unique spike protein configuration and varying degrees of transmissibility and immune evasion. The Omicron variant for instance contains at least 32 mutations in the spike protein, which is twice as many as the Delta variant. The spike from the Alpha variant is more stable against disruption once bound to the ACE2 receptor than all other spikes studied. In the Beta variant spike, the presence of a new mutation, K417N (also observed in the Omicron variant), in combination with the D614G, stabilises a more open conformation, required for receptor binding.

About the artwork

Mimi Haori, a Year 12 student at The Leys School, has developed an artistic interest in the visual characteristics of the spike protein. The distinctive spikes of the virus captivated her, providing a unique artistic challenge that resonated with the complexities of the virus. Mimi's creative process involved the skillful use of paper and acrylic paint, although facing a technical challenge in sculpting a spherical shape solely from paper. Her endeavour illuminated the difficulty of capturing the intricate structure of the spike protein, adding a layer of appreciation for the scientific complexities she aimed to represent.

View the artwork in the virtual 2022 PDB Art exhibition at bit.ly/PDBart2022.

You can also check out the new 2023 PDB art exhibition here.

Structures mentioned in this article

  • 6VXX - SARS-CoV-2 spike in closed state
  • 6VYB - SARS-CoV-2 spike  in open state
  • 7DF4 - SARS-CoV-2 S-ACE2 complex

Sources