Coronavirus: structure-function

The outbreak of a novel coronavirus, COVID-19, has now become a pandemic threat that has been declared a public health emergency of international concern. Although it is hard to predict the future expansion of the COVID-19 pandemic, disease experts agree that it is still going to spread in most places. For an updated live tracking of COVID-19 cases, check out trackcorona.live For a detailed updated overview of the features, evaluation and treatment of COVID-19, you can check out the NCBI page here.

Transmission electron microscope of SARS-CoV-2

Figure 1: This transmission electron microscope image shows SARS-CoV-2, the virus that causes COVID-19—isolated from a patient in the U.S. The spikes on the outer edge of the virus particles give coronaviruses their name, crown-like. Credit: NIAID-RML

There is certainly a lot of similarity between the current COVID-19 virus and the SARS-CoV virus responsible for the 2003 pandemic. They both belong to the Coronavirideae family and have very similar structures and virus replication cycles. All coronaviruses are positive-stranded RNA viruses with a crown-like shape due to the spike glycoproteins on the surface (Figure 1; coronam is the Latin term for crown). However, when we look in more detail at a structural comparison at the biochemical level, we can see some possibly important differences between COVID-19 and the 2003 SARS-CoV virus.

One essential component of the virus infection is the spike protein. These spike proteins are on the surface of coronaviruses and attach the virus to the human cells during infection. After attachment, it fuses with the host cell membrane and releases its own genome into the host cell. Because the spike protein is on the surface and is essential for infection of the host, it is a key target for potential vaccines and diagnostics. Figure 2 shows a structural overlay of the spike protein from COVID-19 (yellow) and SARS from 2003 in blue. Both of these bind the human angiotensin-converting enzyme 2 (ACE2) receptor, but have distinct differences in their affinity for the receptor. The COVID-19 S protein binds ACE2 with higher affinity than does SARS-CoV, which likely contributes to its higher infection rate.

SARS-COVID-19 SpikeOverlay

Figure 2: Structural overlay of the spike protein S from COVID-19 (yellow) and SARS from 2003 (blue). The protein structures were obtained from PDB and rendered with Pymol by J. Kyndt. PDB Accession numbers: PDB6vsb and PDB6crz.

 

Another interesting comparison can be done by looking at the protease that cuts the long viral polypeptide into functional pieces (once it is inside the host cell). This protease also clips several proteins in the infected host cell and is certainly a target for therapeutics. There is a very high amino acid sequence identity (96%) between the COVID-19 coronavirus 3CL hydrolase (Mpro) and the SARS-CoV virus main protease. A structural overlay is shown in figure 3 with COVID-19 Mpro in green and SARS-CoV in red. There are 14 amino acid differences which are shown with their side chains in white.

SARSMproOverlayC

Figure 3: Structural overlay of the main protease MPro from COVID-19 (green) and from SARS (red). Amino acid differences are shown as stick models in white. A known inhibitor of MPro is shown in its binding site in blue. The protein structures were obtained from PDB and rendered with Pymol by J. Kyndt. PDB Accession numbers: PDB6lu7 and PDB1q2w.

Comparisons like these help us understand why this virus is more contagious, but less deadly than SARS, and can eventually give us a potential target for vaccines or therapeutics.

Test your 3D Stereo viewing skills of the coronavirus (Figure 4) and of the protease Mpro and spike protein S (Figures 5 and 6). Position your eyes about a foot away from the screen, stare at the middle of the image and slowly cross your eyes. A third image will appear in the middle in 3D! Keep trying and move closer or further away from the image and eventually you’ll get it.

Stereoscopic Sars-cov-2 virus

Figure 4: Stereoscopic image of a model of the complete SARS-Cov-2 (COVID-19) virus. Just stare at the red pixel in the center, and allow yourself to go cross-eyed!   Stereo rendering by J. Farnen.

SARSMproOverlayStereo

Figure 5: Stereo view of MPro overlay from COVID-19 (green) and SARS (red). Image by J. Kyndt.

SARS SpikeOverlay Stereo

Figure 6: Stereo view of the spike viral protein from COVID-19 (yellow) and SARS (blue). Image by J. Kyndt.

A lot of research is currently ongoing, with many new research and funding opportunities on this topic. For example, the Bill and Melinda Gates foundation recently launched an initiative to speed up the development and access to therapies against COVID-19, this includes a $100 million dollar commitment to the COVID-19 response.

Although there are many scary and worrisome aspects of this current pandemic, in the long run it will eventually lead to a better understanding and valuable scientific lessons to be learned. This is certainly not the last pandemic humankind will experience, afterall we live in a microbial world, but understanding the biochemistry and molecular biology that is underneath these outbreaks might help us to react more efficiently and possibly prevent the fast spread of future viral outbreaks.

Spike COVID-19 spacefill

Space fill model of the COVID-19 Spike protein. Chains A, B and C are colored pink, green and cyan. NAG (N-Acetyl-D-Glucosamine) ligands are colored yellow.                                                            PDB 6vsb rendered in Pymol by J Kyndt.

 

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  1. Pingback: What Makes the Coronavirus Unique? – StudyHacks

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