Sandbox Reserved 1849: Difference between revisions

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==SARS-COV-2 Spike Protein==

<p>The <scene name='10/1075251/Spike_protein_closed_spacefill/4'>spike protein</scene> of SARS-COV-2 is a symmetric trimer featuring 3 spike glycoprotein chains (UNIPROT: [https://www.uniprot.org/uniprotkb/P0DTC2/entry P0DTC2]). Each monomer of the spike is called a spike glycoprotein, and the total assembly contains 2 main parts: The <scene name='10/1075251/Spike_protein_1-up_yang_s1/2'>S1</scene> and <scene name='10/1075251/Spike_protein_1-up_yang_s2/2'>S2</scene> subunits<ref name="Huang">DOI:10.1038/s41401-020-0485-4</ref>. However, the native spike protein does not exist in this state prior to infection. The protein is actually inactive initially, but is later activated by proteases cleaving the inactive S protein into its two active subunits<ref name="Huang">DOI:10.1038/s41401-020-0485-4</ref>. The S1 subunit contains the <scene name='10/1075251/Spike_protein_2-up_yang_s1_dom/2'>N-Terminal domain (NTD), C-Terminal Domain (CTD), and the Receptor Binding Domain (RBD)</scene>. The RBD is responsible for <scene name='10/1075251/Ace2_and_rbd/2'>binding to the ACE2 receptor</scene> on the surface of the target cell, as well as neutralizing antibodies. The NTD, CTD, and their relevant interfaces actually play much larger roles in the binding of the spike protein to ACE2 than the RBD does due to their larger surface areas<ref name="Huang">DOI:10.1038/s41401-020-0485-4</ref>. The S2 subunit is responsible for viral fusion and entry. Once bound to ACE2, and after the different domains in S2 have anchored to the membrane as well as delivered the viral envelope, the S2 subunit then changes conformation from the pre-hairpin to <scene name='10/1075251/Spike_protein_postfusion/2'>postfusion-hairpin</scene> conformation<ref name="Huang">DOI:10.1038/s41401-020-0485-4</ref>. The S2 subunit contains a fusion peptide domain (FP), heptapeptide repeat sequences 1 and 2 (HR1 & HR2), TM domain, and cytoplasmic fusion domain (CT). Full information about the location and structures of these domains within the S2 subunit can be found in references 1 and 3<ref name="Huang">DOI:10.1038/s41401-020-0485-4</ref><ref name="Zhang">PMID:34534731</ref>. For the purpose of this article about the minibinders, attention will be directed to the S1 subunit and its binding properties with ACE2.[[Image:SpikeBFactor.png|250 px|left|rotate=180|thumb|Figure 1. Spike protein shown in "B-Factor"; depicting mobility and flexibility of different portions. Depicted in red are the most mobile, whilst dark blue are the least mobile. The 2 red portions depict RBDs, which correspond to 1-up and 2-up conformational states.]]

[[Image:SpikeBFactor.png|250 px|left|rotate=180|thumb|Figure 1. Spike protein shown in "B-Factor"; depicting mobility and flexibility of different portions. Depicted in red are the most mobile, whilst dark blue are the least mobile. The 2 red portions depict RBDs, which correspond to 1-up and 2-up conformational states.]]

<p>The <scene name='10/1075251/Spike_protein_closed_spacefill/4'>spike protein</scene> of SARS-COV-2 is a symmetric trimer featuring 3 spike glycoprotein chains (UNIPROT: [https://www.uniprot.org/uniprotkb/P0DTC2/entry P0DTC2]). Each monomer of the spike is called a spike glycoprotein, and the total assembly contains 2 main parts: The <scene name='10/1075251/Spike_protein_1-up_yang_s1/2'>S1</scene> and <scene name='10/1075251/Spike_protein_1-up_yang_s2/2'>S2</scene> subunits<ref name="Huang">DOI:10.1038/s41401-020-0485-4</ref>. However, the native spike protein does not exist in this state prior to infection. The protein is actually inactive initially, but is later activated by proteases cleaving the inactive S protein into its two active subunits<ref name="Huang">DOI:10.1038/s41401-020-0485-4</ref>. The S1 subunit contains the <scene name='10/1075251/Spike_protein_2-up_yang_s1_dom/2'>N-Terminal domain (NTD), C-Terminal Domain (CTD), and the Receptor Binding Domain (RBD)</scene>. The RBD is responsible for <scene name='10/1075251/Ace2_and_rbd/2'>binding to the ACE2 receptor</scene> on the surface of the target cell, as well as neutralizing antibodies. The NTD, CTD, and their relevant interfaces actually play much larger roles in the binding of the spike protein to ACE2 than the RBD does due to their larger surface areas<ref name="Huang">DOI:10.1038/s41401-020-0485-4</ref>. The S2 subunit is responsible for viral fusion and entry. Once bound to ACE2, and after the different domains in S2 have anchored to the membrane as well as delivered the viral envelope, the S2 subunit then changes conformation from the pre-hairpin to <scene name='10/1075251/Spike_protein_postfusion/2'>postfusion-hairpin</scene> conformation<ref name="Huang">DOI:10.1038/s41401-020-0485-4</ref>. The S2 subunit contains a fusion peptide domain (FP), heptapeptide repeat sequences 1 and 2 (HR1 & HR2), TM domain, and cytoplasmic fusion domain (CT). Full information about the location and structures of these domains within the S2 subunit can be found in references 1 and 3<ref name="Huang">DOI:10.1038/s41401-020-0485-4</ref><ref name="Zhang">PMID:34534731</ref>. For the purpose of this article about the minibinders, attention will be directed to the S1 subunit and its binding properties with ACE2.

Throughout the entire process, the spike protein has 3 main conformations. An <scene name='10/1075251/Spike_protein_closed_spacefill/5'>inactive, "closed"</scene> conformation; an active, "open" conformation; and a <scene name='10/1075251/Spike_protein_postfusion/2'>post-fusion hairpin</scene> conformation mentioned previously<ref name="Huang">DOI:10.1038/s41401-020-0485-4</ref><ref name="Yuan">PMID:28393837</ref><ref name="Zhang">PMID:34534731</ref>. In the closed conformation, the RBDs of each monomer are tucked inwards, preventing interaction. In the open conformation, however, 1 or more of these RBDs can be in the "up" conformation, meaning they are exposed and able to interact within the extracellular space. Mainly, there exits a "<scene name='10/1075251/Spike_protein_1-up_yang/2'>1-up</scene>" and "<scene name='10/1075251/Spike_protein_2-up_yang/3'>2-up</scene>" conformation in this phase<ref name="Yuan">PMID:28393837</ref><ref name="Zhang">PMID:34534731</ref>. Depicted in Figure 1, the RBDs of the spike protein have the highest mobility, which further support the many conformational changes in which they are involved. Most of the depictions of the minibinders bound to the spike protein show the spike protein in the 2-up conformation.

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 ==SARS-COV-2 Spike Protein==
-<p>The <scene name='10/1075251/Spike_protein_closed_spacefill/4'>spike protein</scene> of SARS-COV-2 is a symmetric trimer featuring 3 spike glycoprotein chains (UNIPROT: [https://www.uniprot.org/uniprotkb/P0DTC2/entry P0DTC2]). Each monomer of the spike is called a spike glycoprotein, and the total assembly contains 2 main parts: The <scene name='10/1075251/Spike_protein_1-up_yang_s1/2'>S1</scene> and <scene name='10/1075251/Spike_protein_1-up_yang_s2/2'>S2</scene> subunits<ref name="Huang">DOI:10.1038/s41401-020-0485-4</ref>. However, the native spike protein does not exist in this state prior to infection. The protein is actually inactive initially, but is later activated by proteases cleaving the inactive S protein into its two active subunits<ref name="Huang">DOI:10.1038/s41401-020-0485-4</ref>. The S1 subunit contains the <scene name='10/1075251/Spike_protein_2-up_yang_s1_dom/2'>N-Terminal domain (NTD), C-Terminal Domain (CTD), and the Receptor Binding Domain (RBD)</scene>. The RBD is responsible for <scene name='10/1075251/Ace2_and_rbd/2'>binding to the ACE2 receptor</scene> on the surface of the target cell, as well as neutralizing antibodies. The NTD, CTD, and their relevant interfaces actually play much larger roles in the binding of the spike protein to ACE2 than the RBD does due to their larger surface areas<ref name="Huang">DOI:10.1038/s41401-020-0485-4</ref>. The S2 subunit is responsible for viral fusion and entry. Once bound to ACE2, and after the different domains in S2 have anchored to the membrane as well as delivered the viral envelope, the S2 subunit then changes conformation from the pre-hairpin to <scene name='10/1075251/Spike_protein_postfusion/2'>postfusion-hairpin</scene> conformation<ref name="Huang">DOI:10.1038/s41401-020-0485-4</ref>. The S2 subunit contains a fusion peptide domain (FP), heptapeptide repeat sequences 1 and 2 (HR1 & HR2), TM domain, and cytoplasmic fusion domain (CT). Full information about the location and structures of these domains within the S2 subunit can be found in references 1 and 3<ref name="Huang">DOI:10.1038/s41401-020-0485-4</ref><ref name="Zhang">PMID:34534731</ref>. For the purpose of this article about the minibinders, attention will be directed to the S1 subunit and its binding properties with ACE2.[[Image:SpikeBFactor.png|250 px|left|rotate=180|thumb|Figure 1. Spike protein shown in "B-Factor"; depicting mobility and flexibility of different portions. Depicted in red are the most mobile, whilst dark blue are the least mobile. The 2 red portions depict RBDs, which correspond to 1-up and 2-up conformational states.]]
+[[Image:SpikeBFactor.png|250 px|left|rotate=180|thumb|Figure 1. Spike protein shown in "B-Factor"; depicting mobility and flexibility of different portions. Depicted in red are the most mobile, whilst dark blue are the least mobile. The 2 red portions depict RBDs, which correspond to 1-up and 2-up conformational states.]]
+<p>The <scene name='10/1075251/Spike_protein_closed_spacefill/4'>spike protein</scene> of SARS-COV-2 is a symmetric trimer featuring 3 spike glycoprotein chains (UNIPROT: [https://www.uniprot.org/uniprotkb/P0DTC2/entry P0DTC2]). Each monomer of the spike is called a spike glycoprotein, and the total assembly contains 2 main parts: The <scene name='10/1075251/Spike_protein_1-up_yang_s1/2'>S1</scene> and <scene name='10/1075251/Spike_protein_1-up_yang_s2/2'>S2</scene> subunits<ref name="Huang">DOI:10.1038/s41401-020-0485-4</ref>. However, the native spike protein does not exist in this state prior to infection. The protein is actually inactive initially, but is later activated by proteases cleaving the inactive S protein into its two active subunits<ref name="Huang">DOI:10.1038/s41401-020-0485-4</ref>. The S1 subunit contains the <scene name='10/1075251/Spike_protein_2-up_yang_s1_dom/2'>N-Terminal domain (NTD), C-Terminal Domain (CTD), and the Receptor Binding Domain (RBD)</scene>. The RBD is responsible for <scene name='10/1075251/Ace2_and_rbd/2'>binding to the ACE2 receptor</scene> on the surface of the target cell, as well as neutralizing antibodies. The NTD, CTD, and their relevant interfaces actually play much larger roles in the binding of the spike protein to ACE2 than the RBD does due to their larger surface areas<ref name="Huang">DOI:10.1038/s41401-020-0485-4</ref>. The S2 subunit is responsible for viral fusion and entry. Once bound to ACE2, and after the different domains in S2 have anchored to the membrane as well as delivered the viral envelope, the S2 subunit then changes conformation from the pre-hairpin to <scene name='10/1075251/Spike_protein_postfusion/2'>postfusion-hairpin</scene> conformation<ref name="Huang">DOI:10.1038/s41401-020-0485-4</ref>. The S2 subunit contains a fusion peptide domain (FP), heptapeptide repeat sequences 1 and 2 (HR1 & HR2), TM domain, and cytoplasmic fusion domain (CT). Full information about the location and structures of these domains within the S2 subunit can be found in references 1 and 3<ref name="Huang">DOI:10.1038/s41401-020-0485-4</ref><ref name="Zhang">PMID:34534731</ref>. For the purpose of this article about the minibinders, attention will be directed to the S1 subunit and its binding properties with ACE2.
 Throughout the entire process, the spike protein has 3 main conformations. An <scene name='10/1075251/Spike_protein_closed_spacefill/5'>inactive, "closed"</scene> conformation; an active, "open" conformation; and a <scene name='10/1075251/Spike_protein_postfusion/2'>post-fusion hairpin</scene> conformation mentioned previously<ref name="Huang">DOI:10.1038/s41401-020-0485-4</ref><ref name="Yuan">PMID:28393837</ref><ref name="Zhang">PMID:34534731</ref>. In the closed conformation, the RBDs of each monomer are tucked inwards, preventing interaction. In the open conformation, however, 1 or more of these RBDs can be in the "up" conformation, meaning they are exposed and able to interact within the extracellular space. Mainly, there exits a "<scene name='10/1075251/Spike_protein_1-up_yang/2'>1-up</scene>" and "<scene name='10/1075251/Spike_protein_2-up_yang/3'>2-up</scene>" conformation in this phase<ref name="Yuan">PMID:28393837</ref><ref name="Zhang">PMID:34534731</ref>. Depicted in Figure 1, the RBDs of the spike protein have the highest mobility, which further support the many conformational changes in which they are involved. Most of the depictions of the minibinders bound to the spike protein show the spike protein in the 2-up conformation.