Coronavirus

A zoonosis is an infectious disease that has jumped from a non-human animal to humans.

A painting by David S. Goodsell showing coronavirus in pink and purple. Secreted mucus (greenish threads) and antibodies (yellow/orange Y-shapes), and several small immune systems proteins (orange) from the lungs’ respiratory cells surround it. © 2020, David S. Goodsell.

The coronavirus disease 2019 (COVID-19) is one such zoonosis, and is caused by severe acute respiratory syndrome coronavirus 2 (SARS coronavirus 2, SARS-CoV-2, or 2019-nCoV). This is very similar to the SARS virus that emerged in 2003. Its recent emergence has resulted in a WHO-declared public health emergency of international concern.

Structural biologists are busy elucidating the structures of the molecular targets of coronavirus, as you can see at the Protein Data Bank. One such target is coronavirus protease, which was featured in David Goodsell’s Molecule of the Month column last month.

SARS-CoV-2 (2019-nCoV) coronavirus main protease, with inhibitor in turquoise. © 2020, David S. Goodsell.

The blueprint for a coronavirus is stored in a long molecule—a single strand of RNA. If the virus is able to infect the right cell, it will hijack its molecular machinery, forcing it to synthesize two long polyproteins. A polyprotein is just another kind of long molecule, made up of amino acids instead of nucleotides. These polyproteins contain the molecular machines and molecular building blocks to make new virus particles (or ‘virions’) inside the infected cell.

One of these molecular machines is the coronavirus main protease, shown above. Its job is to make most of the cuts in the long polyproteins. You can look at and download the structure of the coronavirus main protease of SARS-CoV-2 (or 2019-CoV) from the PDB, at entry 6lu7. Coronavirus main protease is also known as COVID-19 coronavirus 3CL hydrolase (Mpro). In PDB entry 6lu7, it is complexed with an inhibitor:

A peptidomimetic inhibitor of coronavirus main protease, named N3, or N-[(5-methylisoxazol-3-yl)carbonyl]alanyl-L-valyl-N~1~-((1R,2Z)-4-(benzyloxy)-4-oxo-1-{[(3R)-2-oxopyrrolidin-3-yl]methyl}but-2-enyl)-L-leucinamide. This is a Michael acceptor, and also happens to be an inhibitor of human SARS CoV main protease, and feline coronavirus main protease, see PDB entry 5eu8.

The amino acid sequence of COVID-19 coronavirus 3CL hydrolase (Mpro) shares a very high amino acid sequence identity (96%) with the SARS virus main protease (PDB entry 1q2w). The World Wide Protein Data Bank has published a summary CSV file of these closely-related PDB structures.

The COVID-19 structures currently available in the PDB are:

  • 6lu7 (X. Liu, B. Zhang, Z. Jin, H. Yang, Z. Rao Crystal structure of COVID-19 main protease in complex with an inhibitor N3) Released 2020-02-05.
  • 6vsb (D. Wrapp, N. Wang, K.S. Corbett, J.A. Goldsmith, C.-L. Hsieh, O. Abiona, B.S. Graham, J.S. McLellan (2020) Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation, Science, DOI: 10.1126/science.abb2507) Released 2020-02-26.
  • 6lxt (Y. Zhu, F. Sun Structure of post fusion core of 2019-nCoV S2 subunit) Released 2020-02-26.
  • 6lvn (Y. Zhu, F. Sun Structure of the 2019-nCoV HR2 Domain) Released 2020-02-26.

See also the COVID-19 Coronavirus Resources at the PDB.

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