Click above on edit this page to modify. Be careful with the < and > signs. You may include any references to papers as in: the use of JSmol in Proteopedia ^[1] or to the article describing Jmol ^[2] to the rescue.

Introduction

SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) is an RNA virus that is responsible for the highly infectious respiratory disease, COVID-19.

Overall SARS-CoV-2 Structure

It is made up of four structural proteins: spike, envelope, membrane, and nucleocapsid proteins. The spike protein helps the virus infect human cells. The envelope protein helps in virus assembly and release. The membrane protein shapes the viral envelope. The nucleocapsid protein binds the RNA genome for replication. Once inside the cell, virus-specific RNA and proteins are synthesized within the cytoplasm. The viral envelope merges with the oily membrane of our own cells, allowing the virus to release its genetic material into the inside of the healthy cell. The genetic blueprint of the virus is RNA instead of DNA so it gives infected host cells instructions to read the template and translate it to replicate the virus. Each infected cell may produce and release millions of copies of the virus which can infect other neighboring cells and people when the viral particles are released from the airways (i.e., via coughing or sneezing).

Spike Protein

[1]

The spike protein is a glycoprotein that lies on the surface of SARS-CoV-2 to facilitate the entry of the virus into host cells. More specifically, once SARS-CoV-2 has entered the respiratory system, its spike protein binds to the ACE2 receptor (Angiotensin Converting Enzyme Receptor 2) in the lungs. The spike protein is cleaved into two functional subunits: S1 and S2. S1 contains the RBDs (receptor binding domains). S2 plays a key role in membrane fusion between the virus and host cell, allowing viral RNA to enter.

Receptor Binding Domains

The spike protein is a homotrimer with The spike protein’s RBD is the region where it attaches to the human ACE2 receptor.

ACE2 Receptor

the natural receptor for the spike protein, is a membrane-bound protein located in the lungs and made up of 805 amino acids.

Mini Protein Inhibitors

AHB2

is a stable miniprotein inhibitor that competes with the ACE2 receptor. It was developed using the Rosetta blueprint builder that incorporates the alpha helix in ACE2 (residues 23-46) into small, stable protein scaffolds. This allows it to compete with the ACE2 receptor effectively, preventing it from binding with the spike protein and the virus from infecting host cells.

LCB

is a fully synthetic three-helix mini protein that acts as a competitive inhibitor, competing with ACE2 to bind to the spike protein. Unlike ABH2,

Another mini protein inhibitor, was developed using the same computational method as LCB1 and However, LCB1 has more surface area and fits more precisely with its computational model, giving it a slightly higher binding affinity.

The LCBs have a significantly higher affinity for the spike RBD and are smaller and more stable than traditional antibodies. Their reduced size allows these molecules to tightly pack more interactions in the active site as well as improve their ability to enter the respiratory system.

LCB1

LCB3

Binding Interactions

Function

^[3]

^[4]

Therapeutic Relevance

^[3]

^[4]

References

1. ↑ Hanson, R. M., Prilusky, J., Renjian, Z., Nakane, T. and Sussman, J. L. (2013), JSmol and the Next-Generation Web-Based Representation of 3D Molecular Structure as Applied to Proteopedia. Isr. J. Chem., 53:207-216. doi:http://dx.doi.org/10.1002/ijch.201300024
2. ↑ Herraez A. Biomolecules in the computer: Jmol to the rescue. Biochem Mol Biol Educ. 2006 Jul;34(4):255-61. doi: 10.1002/bmb.2006.494034042644. PMID:21638687 doi:10.1002/bmb.2006.494034042644
3. ↑ ^{3.0 3.1} Ransey E, Paredes E, Dey SK, Das SR, Heroux A, Macbeth MR. Crystal structure of the Entamoeba histolytica RNA lariat debranching enzyme EhDbr1 reveals a catalytic Zn(2+) /Mn(2+) heterobinucleation. FEBS Lett. 2017 Jul;591(13):2003-2010. doi: 10.1002/1873-3468.12677. Epub 2017, Jun 14. PMID:28504306 doi:http://dx.doi.org/10.1002/1873-3468.12677
4. ↑ ^{4.0 4.1} Gusev E, Sarapultsev A, Solomatina L, Chereshnev V. SARS-CoV-2-Specific Immune Response and the Pathogenesis of COVID-19. Int J Mol Sci. 2022 Feb 2;23(3):1716. PMID:35163638 doi:10.3390/ijms23031716

Student Contributors

• Carson Powers
• Rachael Vavul

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