Sandbox Reserved 1849: Difference between revisions
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You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue. | You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue. | ||
==Introduction== | ==Introduction== | ||
===What are Minibinders?=== | |||
These mini proteins target the interaction between ACE2 and COVID-19 spike protein <ref name="Longxing">PMID:32907861</ref>. The mini binders are small proteins carefully designed to bind to the COVID-19 spike protein with a greater affinity than ACE2 <ref name="Longxing">PMID:32907861</ref>. These mini binders were able to reduce the viral burden of SARS-CoV-2 in mice <ref name="Case">PMID:34192518</ref>. These proteins were de novo (from scratch) designs to mimic the ACE2 helix, but have a lower dissociation constant, yielding a greater affinity for the spike protein <ref name="Longxing">PMID:32907861</ref>. <scene name='10/1075249/Binding_region/1'>The binding Region between spike protein and ACE2</scene> can give a better explanation as to how these proteins were designed. | |||
===COVID-19 Disease Pathway=== | |||
Understanding the pathway of the COVID-19 virus is essential to understanding the mechanism in which the virus’ surface proteins attach to the mini binders. The COVID-19 virus has spike proteins on its surface that bind to the host cell receptor, known as ACE2, and this allows the virus to remain anchored to the host for viral entry <ref name="Sang">PMID:36499120</ref>. When the spike protein binds to the receptor, ACE2 for example, the cell membrane-associated protease, protease serine 2 TMPRSS2 promotes viral entry by activating the spike protein <ref name="Huang">PMID:32747721</ref>. The activated spike protein is able to cleave itself into S1 and S2 subunits <ref name="Huang">PMID:32747721</ref>. The S2 subunit is in charge of viral entry and does this through conformational changes <ref name="Huang">PMID:32747721</ref>. The S2 subunit will insert it's FP domain into the host cell's membrane, and this will trigger an interaction with the HR2 domain and HR1 trimer to form the 6-helical bundle to bring the viral envelope and cell membrane in close enough distance for viral fusion and ultimately viral entry <ref name="Huang">PMID:32747721</ref>. Once the virus is within the host cell, it is able to translate viral proteins, eliciting an immune response and spreading the viral particles throughout the body <ref name="Huang">PMID:32747721</ref>. | |||
===COVID-19 Viral Infection Interruption=== | |||
The primary goal of the mini binders is to prevent the spike proteins from binding to ACE2, and when the mini binders are bound to the spike protein, the virus is unable to anchor itself to the host protein <ref name="Longxing">PMID:32907861</ref>. Because the mini binders have a greater binding affinity than ACE2 for the spike protein, they are able to effectively prevent the entry of the virus and ultimately prevent an immune response <ref name="Longxing">PMID:32907861</ref>. Targeting this specific interaction between the COVID-19 spike protein has proven effective and is hopeful target for future therapeutics to treat the virus <ref name="Huang">PMID:32747721</ref>. LCB1 proved to be quite effective at weakening the immune response, compared to the other mini binders, which can be explained by the <scene name='10/1075249/Lcb1_and_spike_rbd/1'>binding interface</scene> between the spike protein and LCB1 <ref name="Longxing">PMID:32907861</ref>. | |||
==SARS-COV-2 Spike Protein== | ==SARS-COV-2 Spike Protein== | ||
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As mentioned previously, all of the S1 subunit domains play important roles in the binding to ACE2. The surface area of the NTD and CTD are particularly important, along with the direct interactions observed in the RBD. Whilst ACE2 is not the focus of this article, understanding its role in the infection pathway of COVID 19, as well as how it binds to the spike protein will assist in understanding the design and functional processes of the minibinders. | As mentioned previously, all of the S1 subunit domains play important roles in the binding to ACE2. The surface area of the NTD and CTD are particularly important, along with the direct interactions observed in the RBD. Whilst ACE2 is not the focus of this article, understanding its role in the infection pathway of COVID 19, as well as how it binds to the spike protein will assist in understanding the design and functional processes of the minibinders. | ||
==Minibinders== | ==Minibinders== | ||
===Structure=== | ===Structure=== | ||
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==Design== | ==Design== | ||
These mini binders, LCB1 and AHB2, were designed from “scratch” (de novo) with the intention to mimic the binding of ACE2 to spike protein <ref name="Longxing">PMID:32907861</ref>. Using Rotamer Interaction Field (RIF) docking, the proteins were able to make the most efficient bonding using the ACE2 spike protein binding interface <ref name="Longxing">PMID:32907861</ref>. Using Site Saturation Mutagenesis (SSM), every residue in the minibinder’s helix scaffold will be substituted with each of the 20 amino acids, one at a time <ref name="Valleti">PMID:24970191</ref>. Forming SSM libraries, each of the libraries converged on a small number of closely related sequences, and from these libraries, the design was selected for LCB1 and AHB2 to find the sequence that yields a protein with a high affinity for the spike proteins receptor binding domain <ref name="Longxing">PMID:32907861</ref>. | |||
== Implications == | == Implications == | ||
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</StructureSection> | </StructureSection> | ||
== References == | == References == | ||
<ref name="Longxing">PMID:32907861</ref> | |||
<ref name="Case">PMID:34192518</ref> | |||
<ref name="Sang">PMID:36499120</ref> | |||
<ref name="Huang">DOI:10.1038/s41401-020-0485-4</ref> | <ref name="Huang">DOI:10.1038/s41401-020-0485-4</ref> | ||
<ref name="Yuan">PMID:28393837</ref> | <ref name="Yuan">PMID:28393837</ref> | ||
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<ref name="Kuba ACE2-SARS Pathogenesis">PMID:35003058</ref> | <ref name="Kuba ACE2-SARS Pathogenesis">PMID:35003058</ref> | ||
<ref name="Kuba Lung Injury">PMID:16007097</ref> | <ref name="Kuba Lung Injury">PMID:16007097</ref> | ||
<ref name="Valleti">PMID:24970191</ref> | |||
<references/> | <references/> | ||
