7xog

From Proteopedia

(Difference between revisions)

Current revision

Cryo-EM structure of S glycoprotein encoded by the Covid-19 mRNA vaccine candidate RQ3013 (Postfusion state)

Structural highlights

7xog is a 3 chain structure with sequence from Severe acute respiratory syndrome coronavirus and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.5Å
Ligands:	,
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 global emergence of SARS-CoV-2 variants has led to increasing breakthrough infections in vaccinated populations, calling for an urgent need to develop more effective and broad-spectrum vaccines to combat COVID-19. Here we report the preclinical development of RQ3013, an mRNA vaccine candidate intended to bring broad protection against SARS-CoV-2 variants of concern (VOCs). RQ3013, which contains pseudouridine-modified mRNAs formulated in lipid nanoparticles, encodes the spike (S) protein harboring a combination of mutations responsible for immune evasion of VOCs. Here we characterized the expressed S immunogen and evaluated the immunogenicity, efficacy, and safety of RQ3013 in various animal models. RQ3013 elicited robust immune responses in mice, hamsters, and nonhuman primates (NHP). It can induce high titers of antibodies with broad cross-neutralizing ability against the wild-type, B.1.1.7, B.1.351, B.1.617.2, and the newly emerging Omicron variants. In mice and NHP, two doses of RQ3013 protected the upper and lower respiratory tract against infection by SARS-CoV-2 and its variants. Furthermore, our safety assessment of RQ3013 in NHP showed no observable adverse effects. These results provide strong support for the evaluation of RQ3013 in clinical trials and suggest that it may be a promising candidate for broad protection against COVID-19 and its variants.

Preclinical evaluation of RQ3013, a broad-spectrum mRNA vaccine against SARS-CoV-2 variants.,Tan S, Zhao J, Hu X, Li Y, Wu Z, Lu G, Yu Z, Du B, Liu Y, Li L, Chen Y, Li Y, Yao Y, Zhang X, Rao J, Gao G, Peng Y, Liu H, Yuan Z, Liu J, Wang Q, Hu H, Gao X, Zhou H, Yu H, Xu Y, Yu W, Feng L, Wang M, Shan C, Lu J, Lin J Sci Bull (Beijing). 2023 Dec 30;68(24):3192-3206. doi: , 10.1016/j.scib.2023.11.024. Epub 2023 Nov 14. PMID:37993332^[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
↑ Tan S, Zhao J, Hu X, Li Y, Wu Z, Lu G, Yu Z, Du B, Liu Y, Li L, Chen Y, Li Y, Yao Y, Zhang X, Rao J, Gao G, Peng Y, Liu H, Yuan Z, Liu J, Wang Q, Hu H, Gao X, Zhou H, Yu H, Xu Y, Yu W, Feng L, Wang M, Shan C, Lu J, Lin J. Preclinical evaluation of RQ3013, a broad-spectrum mRNA vaccine against SARS-CoV-2 variants. Sci Bull (Beijing). 2023 Dec 30;68(24):3192-3206. PMID:37993332 doi:10.1016/j.scib.2023.11.024

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/7xog"

Categories: Large Structures | Severe acute respiratory syndrome coronavirus | Synthetic construct | Lin J | Lu G | Lu J | Tan S | Wu Z | Yu Z

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 7xog is ON HOLD
+==Cryo-EM structure of S glycoprotein encoded by the Covid-19 mRNA vaccine candidate RQ3013 (Postfusion state)==
+<StructureSection load='7xog' size='340' side='right'caption='[[7xog]], [[Resolution|resolution]] 3.50&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[7xog]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Severe_acute_respiratory_syndrome_coronavirus Severe acute respiratory syndrome coronavirus] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7XOG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7XOG FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.5&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></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=7xog FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7xog OCA], [https://pdbe.org/7xog PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7xog RCSB], [https://www.ebi.ac.uk/pdbsum/7xog PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7xog 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 global emergence of SARS-CoV-2 variants has led to increasing breakthrough infections in vaccinated populations, calling for an urgent need to develop more effective and broad-spectrum vaccines to combat COVID-19. Here we report the preclinical development of RQ3013, an mRNA vaccine candidate intended to bring broad protection against SARS-CoV-2 variants of concern (VOCs). RQ3013, which contains pseudouridine-modified mRNAs formulated in lipid nanoparticles, encodes the spike (S) protein harboring a combination of mutations responsible for immune evasion of VOCs. Here we characterized the expressed S immunogen and evaluated the immunogenicity, efficacy, and safety of RQ3013 in various animal models. RQ3013 elicited robust immune responses in mice, hamsters, and nonhuman primates (NHP). It can induce high titers of antibodies with broad cross-neutralizing ability against the wild-type, B.1.1.7, B.1.351, B.1.617.2, and the newly emerging Omicron variants. In mice and NHP, two doses of RQ3013 protected the upper and lower respiratory tract against infection by SARS-CoV-2 and its variants. Furthermore, our safety assessment of RQ3013 in NHP showed no observable adverse effects. These results provide strong support for the evaluation of RQ3013 in clinical trials and suggest that it may be a promising candidate for broad protection against COVID-19 and its variants.
-Authors: Wu, Z., Yu, Z., Tan, S., Lu, J., Lu, G., Lin, J.
+Preclinical evaluation of RQ3013, a broad-spectrum mRNA vaccine against SARS-CoV-2 variants.,Tan S, Zhao J, Hu X, Li Y, Wu Z, Lu G, Yu Z, Du B, Liu Y, Li L, Chen Y, Li Y, Yao Y, Zhang X, Rao J, Gao G, Peng Y, Liu H, Yuan Z, Liu J, Wang Q, Hu H, Gao X, Zhou H, Yu H, Xu Y, Yu W, Feng L, Wang M, Shan C, Lu J, Lin J Sci Bull (Beijing). 2023 Dec 30;68(24):3192-3206. doi: , 10.1016/j.scib.2023.11.024. Epub 2023 Nov 14. PMID:37993332<ref>PMID:37993332</ref>
-Description: Cryo-EM structure of S glycoprotein encoded by the Covid-19 mRNA vaccine candidate RQ3013 (Postfusion state)
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Tan, S]]
+<div class="pdbe-citations 7xog" style="background-color:#fffaf0;"></div>
-[[Category: Lin, J]]
+== References ==
-[[Category: Yu, Z]]
+<references/>
-[[Category: Wu, Z]]
+__TOC__
-[[Category: Lu, G]]
+</StructureSection>
-[[Category: Lu, J]]
+[[Category: Large Structures]]
+[[Category: Severe acute respiratory syndrome coronavirus]]
+[[Category: Synthetic construct]]
+[[Category: Lin J]]
+[[Category: Lu G]]
+[[Category: Lu J]]
+[[Category: Tan S]]
+[[Category: Wu Z]]
+[[Category: Yu Z]]

7xog

From Proteopedia

Current revision

Cryo-EM structure of S glycoprotein encoded by the Covid-19 mRNA vaccine candidate RQ3013 (Postfusion state)

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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