Coronavirus Disease 2019 (COVID-19)

spinqualitylabelsall models Morph showing the transition of SARS-CoV-2 spike protein from its closed to open conformation induced by proteolytic cleavage, details at SARS-CoV-2_spike_protein_priming_by_furin Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

A novel coronavirus SARS-CoV-2, detected in Wuhan, China in 2019, was found to cause severe respiratory illness named COVID-19^[1].

There’s a new NCBI site on COVID-19/SARS-CoV-2. It will help bench scientists, bioinformaticians, clinicians & others connect with information they need to study SARS-CoV-2 and end the pandemic.

A video (by Elara) shows how the virus interacts with its human (host) cells, via its spike proteins^{[2][3][4][5][6][7]}, thus permitting the viral genome to enter its host & begin infection. The spike protein is induced for optimal binding when it is clipped by a protease (see animation on right side) and more details at SARS-CoV-2_protein_S_activation_by_furin. Subsequently, it undergoes a dramatic transformation to induce membrane fusion and infection, explained with a morph animation at SARS-CoV-2 spike protein fusion transformation.

Contents 1 Useful sites on COVID-19 2 Potential treatments for COVID-19 3 3D structural studies on SARS-CoV-2 virus 4 SARS-CoV-2 virus proteins 5 References

Useful sites on COVID-19

• A plot of the number of COVID-19 deaths per million people as reported at the Hopkins Web Site, Surprisingly, Israel and USA have the highest numbers.
  

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• A series of fascinating COVID-19 Videos.

• COVID-19 AlphaFold2 Models that have been of structures of SARS CoV-2 proteins whose structure have not yet been experimentally determined.

• Up to date statistics on Coronavirus cases world-wide at worldometer

• A summary of key findings about COVID-19 can be found at the CDC.

• Coronavirus Evolved Naturally, and ‘Is Not a Laboratory Construct,’ in a study in Nature Med by Anderson and colleagues ^[9].

Potential treatments for COVID-19

• COVID-19: What are our therapeutic options? - Slides courtesy of Prof. Mamta K. Jain, MD, MPH, UT Southwestern Medical Center.

• An int'l group of scientists (UK, Israel & USA) are trying to combat COVID-19 via a massive crystal-based fragment screen. They determined 3D structures of over 90 fragments with 66 in the active site. Details are available at the Diamond Light Source. Contributions are welcome in many different forms PostEra.

• 31-Mar-2020 NY Times C.D.C. Weighs Advising Everyone to Wear a Mask.

3D structural studies on SARS-CoV-2 virus

The quality of SARS-CoV-2 experimentally determined structures varies widely (Grabowski et al., 2021). Validated and corrected structures can be obtained from COVID19.BioReproducibility.Org.

• A team of UK & Israeli scientists determined the 3D structures of over 90 fragments, 66 of which are in the active site. All the experimental details and results are available online at the Diamond Light Source'.

• A team of Chinese scientists determined, by Cryo-EM, the coronavirus spike receptor-binding domain complexed with its receptor ACE2 PDB-ID 6lzg (To be published).

• A team of US and Chinese scientists determined the crystal structure of 2019-nCoV spike receptor-binding domain bound with ACE2 6m0j

• A team of US scientists determined, by Cryo-EM, the structure of the SARS-CoV-2 spike glycoprotein (open & closed states) ^[10], PDB-ID 6vxx and 6vyb. See an animation of this transition.

• Crystal structure of SARS-CoV-2 receptor binding domain in complex with human antibody CR3022 6w41

• Crystal Structure of the methyltransferase-stimulatory factor complex of NSP16 and NSP10 from SARS CoV-2 6w61 (To be published).

• Crystal Structure of ADP ribose phosphatase of NSP3 from SARS CoV-2 in complex with AMP 6w6y (To be published).

• Structure of NSP10 - NSP16 Complex from SARS-CoV-2 6w75 (To be published).

• Crystal structure of SARS-CoV-2 nucleocapsid protein N-terminal RNA binding domain 6m3m (To be published).

• Crystal structure of Nsp9 RNA binding protein of SARS CoV-2 6w4b (To be published).

• Crystal Structure of NSP16 - NSP10 Complex from SARS-CoV-2 6w4h (To be published).

• A Cryo-EM study by Zhou & colleagues on the structural basis for the recognition of the SARS-CoV-2 by full-length human ACE2 gives insights to the molecular basis for coronavirus recognition and infection^[11] 6m17.

• Crystal structure of RNA binding domain of nucleocapsid phosphoprotein from SARS coronavirus 2 6vyo (To be published).

• Crystal structure of NSP15 Endoribonuclease from SARS CoV-2 in the Complex with a Citrate 6w01 (To be published).

• Crystal structure of ADP ribose phosphatase of NSP3 from SARS CoV-2 in the complex with ADP ribose 6w02 (To be published).

• Crystal structure of 2019-nCoV chimeric receptor-binding domain complexed with its receptor human ACE2 6vw1

• Crystal structure of NSP15 Endoribonuclease from SARS CoV-2 6vww (To be published).

• Crystal Structure of ADP ribose phosphatase of NSP3 from SARS CoV-2 6vxs (To be published).

• Crystal structure of the 2019-nCoV HR2 Domain 6lvn (To be published).

• Crystal structure of post fusion core of 2019-nCoV S2 subunit 6lxt.

• Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors, from the Hilgenfeld lab^[12], Apo Struture: PDB-ID 6y2e, and complexes with inhibitors: PDB-ID 6y2f and 6y2g.

• 3D Structure of RNA-dependent RNA polymerase from COVID-19, a major antiviral drug target from the Rao lab in Beijing^[13].

• Crystal structure of the Mpro from COVID-19 and discovery of inhibitors in a study by scientists from Shanghai & Beijing^[14], PDB-ID 6lu7.

• Crystal structure of Nsp15 endoribonuclease NendoU from SARS-CoV-2 in a study by scientists from USA^[15], PDB-ID 6w01.

• The CoV spike (S) glycoprotein is a key target for vaccines, therapeutic antibodies, and diagnostics. A study by McLellan and colleagues in "Science" on the Cryo-EM structure of the COVID-19 spike protein. This structure should greatly aid in the rapid development and evaluation of medical countermeasures to address the ongoing public health crisis^[3], PDB-ID 6vsb.

• Public resource for the structures from beta-coronavirus with a focus on SARS-CoV and SARS-CoV-2

SARS-CoV-2 virus proteins

The quality of SARS-CoV-2 experimentally determined structures varies widely (Grabowski et al., 2021). Validated and corrected structures can be obtained from COVID19.BioReproducibility.Org.

The genome of the SARS-CoV-2 virus codes for 28 proteins: Out of those, 19 have already been characterized structurally.
Details of the 3D structure & function of the key proteins & RNA inside the virus can be seen in the NY Times Bad News Wrapped in Protein: Inside the Coronavirus Genome.

• Main protease: it is a cysteine protease that is essential for the viral life cycle.
• NSP1: Host translation inhibitor nsp1. Inhibits host translation by interacting with the 40S ribosomal subunit.
• NSP2: Non-structural protein 2.
• Papain-like proteinase
• NSP4: Non-structural protein 4.
• Proteinase 3CL-PRO
• AlphaFold2 Theoretical Model NSP6: Non-structural protein 6.
• NSP7: Non-structural protein 7.
• NSP8: Non-structural protein 8.
• NSP9: Non-structural protein 9.
• NSP10: Non-structural protein 10.
• RNA-directed RNA polymerase (RdRp)
• Helicase (Hel): Multi-functional protein with a zinc-binding domain in N-terminus
• Guanine-N7 methyltransferase (ExoN)
• Uridylate-specific endoribonuclease (NendoU)
• 2'-O-methyltransferase (2'-O-MT): Methyltransferase that mediates mRNA cap 2'-O-ribose methylation to the 5'-cap structure of viral mRNAs.
• Surface glycoprotein (S) and SARS-CoV-2 protein S priming by furin
• ORF3a: Forms homotetrameric potassium sensitive ion channels (viroporin) and may modulate virus release.
• Protein E: Plays a central role in virus morphogenesis and assembly.
• AlphaFold2 Theoretical Model Protein M: Component of the viral envelope.
• ORF6: Could be a determinant of virus virulence.
• ORF7a: Non-structural protein which is dispensable for virus replication in cell culture.
• ORF8: Open Reading Frame 8.
• AlphaFold2 Theoretical Model Protein N: Packages the positive strand viral genome RNA into a helical ribonucleocapsid (RNP).
• AlphaFold2 Theoretical Model ORF10‎: It is currently unclear whether this region translates into a functional protein.

References

1. ↑ Naming the coronavirus disease (COVID-19) and the virus that causes it
2. ↑ Pillay TS. Gene of the month: the 2019-nCoV/SARS-CoV-2 novel coronavirus spike protein. J Clin Pathol. 2020 Jul;73(7):366-369. doi: 10.1136/jclinpath-2020-206658. Epub, 2020 May 6. PMID:32376714 doi:http://dx.doi.org/10.1136/jclinpath-2020-206658
3. ↑ ^{3.0 3.1} Wrapp D, Wang N, Corbett KS, Goldsmith JA, Hsieh CL, Abiona O, Graham BS, McLellan JS. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science. 2020 Feb 19. pii: science.abb2507. doi: 10.1126/science.abb2507. PMID:32075877 doi:http://dx.doi.org/10.1126/science.abb2507
4. ↑ Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D. Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell. 2020 Mar 6. pii: S0092-8674(20)30262-2. doi: 10.1016/j.cell.2020.02.058. PMID:32155444 doi:http://dx.doi.org/10.1016/j.cell.2020.02.058
5. ↑ Wrobel AG, Benton DJ, Xu P, Roustan C, Martin SR, Rosenthal PB, Skehel JJ, Gamblin SJ. SARS-CoV-2 and bat RaTG13 spike glycoprotein structures inform on virus evolution and furin-cleavage effects. Nat Struct Mol Biol. 2020 Jul 9. pii: 10.1038/s41594-020-0468-7. doi:, 10.1038/s41594-020-0468-7. PMID:32647346 doi:http://dx.doi.org/10.1038/s41594-020-0468-7
6. ↑ Thomas G. Furin at the cutting edge: from protein traffic to embryogenesis and disease. Nat Rev Mol Cell Biol. 2002 Oct;3(10):753-66. doi: 10.1038/nrm934. PMID:12360192 doi:http://dx.doi.org/10.1038/nrm934
7. ↑ Wang Q, Zhang Y, Wu L, Niu S, Song C, Zhang Z, Lu G, Qiao C, Hu Y, Yuen KY, Wang Q, Zhou H, Yan J, Qi J. Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2. Cell. 2020 Apr 7. pii: S0092-8674(20)30338-X. doi: 10.1016/j.cell.2020.03.045. PMID:32275855 doi:http://dx.doi.org/10.1016/j.cell.2020.03.045
8. ↑ JHU COVID-19 Web Site https://ourworldindata.org/grapher/weekly-covid-deaths-per-million-people
9. ↑ Andersen, et al. The proximal origin of SARS-CoV-2: Nature Med (in press) 2020 http://dx.doi.org/10.1038/s41591-020-0820-9]
10. ↑ Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D. Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell. 2020 Mar 6. pii: S0092-8674(20)30262-2. doi: 10.1016/j.cell.2020.02.058. PMID:32155444 doi:http://dx.doi.org/10.1016/j.cell.2020.02.058
11. ↑ Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of the SARS-CoV-2 by full-length human ACE2. Science. 2020 Mar 4. pii: science.abb2762. doi: 10.1126/science.abb2762. PMID:32132184 doi:http://dx.doi.org/10.1126/science.abb2762
12. ↑ Zhang L, Lin D, Sun X, Curth U, Drosten C, Sauerhering L, Becker S, Rox K, Hilgenfeld R. Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved alpha-ketoamide inhibitors. Science. 2020 Mar 20. pii: science.abb3405. doi: 10.1126/science.abb3405. PMID:32198291 doi:http://dx.doi.org/10.1126/science.abb3405
13. ↑ Gao, et al. Structure of RNA-dependent RNA polymerase from 2019-nCoV, a major antiviral drug target: bioRxiv (online) 2020 http://doi.org/10.1101/2020.03.16.993386
14. ↑ Jin Z, Du X, Xu Y, Deng Y, Liu M, Zhao Y, Zhang B, Li X, Zhang L, Peng C, Duan Y, Yu J, Wang L, Yang K, Liu F, Jiang R, Yang X, You T, Liu X, Yang X, Bai F, Liu H, Liu X, Guddat LW, Xu W, Xiao G, Qin C, Shi Z, Jiang H, Rao Z, Yang H. Structure of M(pro) from COVID-19 virus and discovery of its inhibitors. Nature. 2020 Apr 9. pii: 10.1038/s41586-020-2223-y. doi:, 10.1038/s41586-020-2223-y. PMID:32272481 doi:http://dx.doi.org/10.1038/s41586-020-2223-y
15. ↑ Kim, et al. Crystal structure of Nsp15 endoribonuclease NendoU from SARS-CoV-2: bioRxiv (online) 2020 http://doi.org/10.1101/2020.03.02.968388