PTNG Consulting

Like many scientific communities, structural biologists have responded extraordinarily quickly in the fight against the coronavirus (SARS-CoV-2, also referred to as 2019-nCoV) and the resultant disease COVID-19, by determining the structure of many of the viral proteins. Put simply, understanding the structures of these proteins will underpin our understanding of this virus and how to combat it with drugs and vaccines. I’ve been following the science using a few key resources that have been created especially for the crisis:

LitCovid (Peer-reviewed COVID-19 publications)
Protein Data Bank (PDB)
Coronavirus Structural Taskforce
NIH COVID-19 resource
ViPR (Virus Pathogen Resource)
Swiss Institute of Bioinformatics ViralZone
EMBL-EBI Datahub
Cell Press Coronavirus Resource Hub
Science Magazine
Proceedings of the National Academy of Sciences
bioRxiv preprint server

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As of writing the proteome of SARS-Co-V-2 consists of 27 proteins (see annotation).

Over the past week the number of COVID19-related structures deposited in the Protein Data Bank (PDB) has grown extremely quickly - currently there are 104 structures deposited. Impressively, there are 69 structures for the main protease in complex with ligands or inhibitors. This is important because it represents a crucial step in the process of rational drug design – more on that in a later post.

As one might expect, the vast majority (100) of these are from X-ray crystallographic data, however 4 are from Electron microscopy (EM)  – this is testament to the “resolution revolution” and the emergence of EM as a powerful tool in structural biology. All of these EM structures are of the virus spike glycoprotein, which comprises the receptor binding domain and is thus the molecule that targets the receptors on human cells. This in an important piece of the puzzle – structural knowledge of this molecule is key to making vaccines, and also antibodies that might neutralize the virus. More on this in an upcoming post. For now, here is a gallery showing the different folds represented by COVID19-related structures deposited in the PDB so far:

Top left: Post fusion core of S2 subunit - RNA transcription and replication

Top middle: NSP15 Endoribonuclease - RNA transcription and replication

Top right: RNA binding domain of nucleocapsid phosphoprotein - RNA transcription and replication

Middle left: spike ectodomain structure (open state) - Viral entry into host cells

Centre: Nsp9 RNA binding protein - RNA transcription and replication

Middle right: NSP3 ADP ribose phosphatase – Virus budding

Bottom left: Methyltransferase-stimulatory factor complex of NSP16 (blue)-NSP10 (red) - RNA transcription and replication

Bottom middle: Spike receptor-binding domain (orange) complexed with its receptor ACE2 (green) - Viral entry into host cells

Bottom right: Main protease - polyprotein cleavage