7mtc

From Proteopedia

(Difference between revisions)

Revision as of 12:54, 13 October 2021

Structure of freshly purified SARS-CoV-2 S2P spike at pH 7.4

Structural highlights

7mtc is a 3 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	7mtd, 7mte
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[SPIKE_SARS2] attaches the virion to the cell membrane by interacting with host receptor, initiating the infection (By similarity). Binding to human ACE2 receptor and internalization of the virus into the endosomes of the host cell induces conformational changes in the Spike glycoprotein (PubMed:32142651, PubMed:32075877, PubMed:32155444). Uses also human TMPRSS2 for priming in human lung cells which is an essential step for viral entry (PubMed:32142651). Proteolysis by cathepsin CTSL may unmask the fusion peptide of S2 and activate membranes fusion within endosomes.[HAMAP-Rule:MF_04099]^[1] ^[2] ^[3] mediates fusion of the virion and cellular membranes by acting as a class I viral fusion protein. Under the current model, the protein has at least three conformational states: pre-fusion native state, pre-hairpin intermediate state, and post-fusion hairpin state. During viral and target cell membrane fusion, the coiled coil regions (heptad repeats) assume a trimer-of-hairpins structure, positioning the fusion peptide in close proximity to the C-terminal region of the ectodomain. The formation of this structure appears to drive apposition and subsequent fusion of viral and target cell membranes.[HAMAP-Rule:MF_04099] Acts as a viral fusion peptide which is unmasked following S2 cleavage occurring upon virus endocytosis.[HAMAP-Rule:MF_04099]

Publication Abstract from PubMed

The SARS-CoV-2 spike is the primary target of virus-neutralizing antibodies and critical to the development of effective vaccines against COVID-19. Here, we demonstrate that the prefusion-stabilized two-proline "S2P" spike -widely employed for laboratory work and clinical studies- unfolds when stored at 4 degrees C, physiological pH, as observed by electron microscopy (EM) and differential scanning calorimetry, but that its trimeric, native-like conformation can be reacquired by low pH treatment. When stored for approximately one week, this unfolding does not significantly alter antigenic characteristics; however, longer storage diminishes antibody binding, and month-old spike elicits virtually no neutralization in mice despite inducing high ELISA-binding titers. Cryo-EM structures reveal the folded fraction of spike to decrease with aging, though its structure remains largely similar, although with varying mobility of the receptor-binding domain. Thus, the SARS-CoV-2 spike is susceptible to unfolding which affects immunogenicity, highlighting the need to monitor its integrity.

SARS-CoV-2 S2P spike ages through distinct states with altered immunogenicity.,Olia AS, Tsybovsky Y, Chen SJ, Liu C, Nazzari AF, Ou L, Wang L, Kong WP, Leung K, Liu T, Stephens T, Teng IT, Wang S, Yang ES, Zhang B, Zhang Y, Zhou T, Mascola JR, Kwong PD J Biol Chem. 2021 Aug 27:101127. doi: 10.1016/j.jbc.2021.101127. PMID:34461095^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ 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
↑ Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, Muller MA, Drosten C, Pohlmann S. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020 Apr 16;181(2):271-280.e8. doi: 10.1016/j.cell.2020.02.052. Epub 2020, Mar 5. PMID:32142651 doi:http://dx.doi.org/10.1016/j.cell.2020.02.052
↑ 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
↑ Olia AS, Tsybovsky Y, Chen SJ, Liu C, Nazzari AF, Ou L, Wang L, Kong WP, Leung K, Liu T, Stephens T, Teng IT, Wang S, Yang ES, Zhang B, Zhang Y, Zhou T, Mascola JR, Kwong PD. SARS-CoV-2 S2P spike ages through distinct states with altered immunogenicity. J Biol Chem. 2021 Aug 27:101127. doi: 10.1016/j.jbc.2021.101127. PMID:34461095 doi:http://dx.doi.org/10.1016/j.jbc.2021.101127

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7mtc"

@@ Line 1: / Line 1: @@
 ==Structure of freshly purified SARS-CoV-2 S2P spike at pH 7.4==
-<StructureSection load='7mtc' size='340' side='right'caption='[[7mtc]]' scene=''>
+<StructureSection load='7mtc' size='340' side='right'caption='[[7mtc]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7MTC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MTC FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7mtc]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7MTC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MTC FirstGlance]. <br>
-</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7mtc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7mtc OCA], [https://pdbe.org/7mtc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7mtc RCSB], [https://www.ebi.ac.uk/pdbsum/7mtc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7mtc ProSAT]</span></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[7mtd|7mtd]], [[7mte|7mte]]</div></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7mtc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7mtc OCA], [https://pdbe.org/7mtc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7mtc RCSB], [https://www.ebi.ac.uk/pdbsum/7mtc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7mtc ProSAT]</span></td></tr>
 </table>
+== Function ==
+[[https://www.uniprot.org/uniprot/SPIKE_SARS2 SPIKE_SARS2]] attaches the virion to the cell membrane by interacting with host receptor, initiating the infection (By similarity). Binding to human ACE2 receptor and internalization of the virus into the endosomes of the host cell induces conformational changes in the Spike glycoprotein (PubMed:32142651, PubMed:32075877, PubMed:32155444). Uses also human TMPRSS2 for priming in human lung cells which is an essential step for viral entry (PubMed:32142651). Proteolysis by cathepsin CTSL may unmask the fusion peptide of S2 and activate membranes fusion within endosomes.[HAMAP-Rule:MF_04099]<ref>PMID:32075877</ref> <ref>PMID:32142651</ref> <ref>PMID:32155444</ref>   mediates fusion of the virion and cellular membranes by acting as a class I viral fusion protein. Under the current model, the protein has at least three conformational states: pre-fusion native state, pre-hairpin intermediate state, and post-fusion hairpin state. During viral and target cell membrane fusion, the coiled coil regions (heptad repeats) assume a trimer-of-hairpins structure, positioning the fusion peptide in close proximity to the C-terminal region of the ectodomain. The formation of this structure appears to drive apposition and subsequent fusion of viral and target cell membranes.[HAMAP-Rule:MF_04099]  Acts as a viral fusion peptide which is unmasked following S2 cleavage occurring upon virus endocytosis.[HAMAP-Rule:MF_04099]
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+The SARS-CoV-2 spike is the primary target of virus-neutralizing antibodies and critical to the development of effective vaccines against COVID-19. Here, we demonstrate that the prefusion-stabilized two-proline "S2P" spike -widely employed for laboratory work and clinical studies- unfolds when stored at 4 degrees C, physiological pH, as observed by electron microscopy (EM) and differential scanning calorimetry, but that its trimeric, native-like conformation can be reacquired by low pH treatment. When stored for approximately one week, this unfolding does not significantly alter antigenic characteristics; however, longer storage diminishes antibody binding, and month-old spike elicits virtually no neutralization in mice despite inducing high ELISA-binding titers. Cryo-EM structures reveal the folded fraction of spike to decrease with aging, though its structure remains largely similar, although with varying mobility of the receptor-binding domain. Thus, the SARS-CoV-2 spike is susceptible to unfolding which affects immunogenicity, highlighting the need to monitor its integrity.
+SARS-CoV-2 S2P spike ages through distinct states with altered immunogenicity.,Olia AS, Tsybovsky Y, Chen SJ, Liu C, Nazzari AF, Ou L, Wang L, Kong WP, Leung K, Liu T, Stephens T, Teng IT, Wang S, Yang ES, Zhang B, Zhang Y, Zhou T, Mascola JR, Kwong PD J Biol Chem. 2021 Aug 27:101127. doi: 10.1016/j.jbc.2021.101127. PMID:34461095<ref>PMID:34461095</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 7mtc" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
 __TOC__
 </StructureSection>
 [[Category: Large Structures]]
-[[Category: Kwong PD]]
+[[Category: Kwong, P D]]
-[[Category: Olia AS]]
+[[Category: Olia, A S]]
-[[Category: Tsybovsky Y]]
+[[Category: Tsybovsky, Y]]
+[[Category: Covid-19]]
+[[Category: S2p]]
+[[Category: Sars-cov-2 spike]]
+[[Category: Viral protein]]

7mtc

From Proteopedia

Revision as of 12:54, 13 October 2021

Structure of freshly purified SARS-CoV-2 S2P spike at pH 7.4

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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