9aru

From Proteopedia

(Difference between revisions)

Current revision

COVA2-15 fragment antigen binding in complex with SARS-CoV-2 6P-mut7 S protein

Structural highlights

9aru is a 9 chain structure with sequence from Homo sapiens and Severe acute respiratory syndrome coronavirus 2. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.9Å
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

Prevention of severe COVID-19 disease by SARS-CoV-2 in high-risk patients, such as immuno-compromised individuals, can be achieved by administration of antibody prophylaxis, but producing antibodies can be costly. Plant expression platforms allow substantial lower production costs compared to traditional bio-manufacturing platforms depending on mammalian cells in bioreactors. In this study, we describe the expression, production and purification of the originally human COVA2-15 antibody in plants. Our plant-produced mAbs demonstrated comparable neutralizing activity with COVA2-15 produced in mammalian cells. Furthermore, they exhibited similar capacity to prevent SARS-CoV-2 infection in a hamster model. To further enhance these biosimilars, we performed three glyco- and protein engineering techniques. First, to increase antibody half-life, we introduced YTE-mutation in the Fc tail; second, optimization of N-linked glycosylation by the addition of a C-terminal ER-retention motif (HDEL), and finally; production of mAb in plant production lines lacking beta-1,2-xylosyltransferase and alpha-1,3-fucosyltransferase activities (FX-KO). These engineered biosimilars exhibited optimized glycosylation, enhanced phagocytosis and NK cell activation capacity compared to conventional plant-produced S15 and M15 biosimilars, in some cases outperforming mammalian cell produced COVA2-15. These engineered antibodies hold great potential for enhancing in vivo efficacy of mAb treatment against COVID-19 and provide a platform for the development of antibodies against other emerging viruses in a cost-effective manner.

Plant-produced SARS-CoV-2 antibody engineered towards enhanced potency and in vivo efficacy.,de Taeye SW, Faye L, Morel B, Schriek AI, Umotoy JC, Yuan M, Kuzmina NA, Turner HL, Zhu X, Grunwald-Gruber C, Poniman M, Burger JA, Caniels TG, Fitchette AC, Desgagnes R, Stordeur V, Mirande L, Beauverger G, de Bree G, Ozorowski G, Ward AB, Wilson IA, Bukreyev A, Sanders RW, Vezina LP, Beaumont T, van Gils MJ, Gomord V Plant Biotechnol J. 2024 Nov 19. doi: 10.1111/pbi.14458. PMID:39563066^[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
↑ de Taeye SW, Faye L, Morel B, Schriek AI, Umotoy JC, Yuan M, Kuzmina NA, Turner HL, Zhu X, Grünwald-Gruber C, Poniman M, Burger JA, Caniels TG, Fitchette AC, Desgagnés R, Stordeur V, Mirande L, Beauverger G, de Bree G, Ozorowski G, Ward AB, Wilson IA, Bukreyev A, Sanders RW, Vezina LP, Beaumont T, van Gils MJ, Gomord V. Plant-produced SARS-CoV-2 antibody engineered towards enhanced potency and in vivo efficacy. Plant Biotechnol J. 2024 Nov 19. PMID:39563066 doi:10.1111/pbi.14458

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/9aru"

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 9aru is ON HOLD  until Paper Publication
+==COVA2-15 fragment antigen binding in complex with SARS-CoV-2 6P-mut7 S protein==
+<StructureSection load='9aru' size='340' side='right'caption='[[9aru]], [[Resolution|resolution]] 3.90&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[9aru]] is a 9 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Severe_acute_respiratory_syndrome_coronavirus_2 Severe acute respiratory syndrome coronavirus 2]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9ARU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9ARU 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]] 3.9&#8491;</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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9aru FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9aru OCA], [https://pdbe.org/9aru PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9aru RCSB], [https://www.ebi.ac.uk/pdbsum/9aru PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9aru 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 ==
+Prevention of severe COVID-19 disease by SARS-CoV-2 in high-risk patients, such as immuno-compromised individuals, can be achieved by administration of antibody prophylaxis, but producing antibodies can be costly. Plant expression platforms allow substantial lower production costs compared to traditional bio-manufacturing platforms depending on mammalian cells in bioreactors. In this study, we describe the expression, production and purification of the originally human COVA2-15 antibody in plants. Our plant-produced mAbs demonstrated comparable neutralizing activity with COVA2-15 produced in mammalian cells. Furthermore, they exhibited similar capacity to prevent SARS-CoV-2 infection in a hamster model. To further enhance these biosimilars, we performed three glyco- and protein engineering techniques. First, to increase antibody half-life, we introduced YTE-mutation in the Fc tail; second, optimization of N-linked glycosylation by the addition of a C-terminal ER-retention motif (HDEL), and finally; production of mAb in plant production lines lacking beta-1,2-xylosyltransferase and alpha-1,3-fucosyltransferase activities (FX-KO). These engineered biosimilars exhibited optimized glycosylation, enhanced phagocytosis and NK cell activation capacity compared to conventional plant-produced S15 and M15 biosimilars, in some cases outperforming mammalian cell produced COVA2-15. These engineered antibodies hold great potential for enhancing in vivo efficacy of mAb treatment against COVID-19 and provide a platform for the development of antibodies against other emerging viruses in a cost-effective manner.
-Authors: Ozorowski, G., Turner, H.L., Ward, A.B.
+Plant-produced SARS-CoV-2 antibody engineered towards enhanced potency and in vivo efficacy.,de Taeye SW, Faye L, Morel B, Schriek AI, Umotoy JC, Yuan M, Kuzmina NA, Turner HL, Zhu X, Grunwald-Gruber C, Poniman M, Burger JA, Caniels TG, Fitchette AC, Desgagnes R, Stordeur V, Mirande L, Beauverger G, de Bree G, Ozorowski G, Ward AB, Wilson IA, Bukreyev A, Sanders RW, Vezina LP, Beaumont T, van Gils MJ, Gomord V Plant Biotechnol J. 2024 Nov 19. doi: 10.1111/pbi.14458. PMID:39563066<ref>PMID:39563066</ref>
-Description: COVA2-15 fragment antigen binding in complex with SARS-CoV-2 6P-mut7 S protein
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Ozorowski, G]]
+<div class="pdbe-citations 9aru" style="background-color:#fffaf0;"></div>
-[[Category: Turner, H.L]]
+== References ==
-[[Category: Ward, A.B]]
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Severe acute respiratory syndrome coronavirus 2]]
+[[Category: Ozorowski G]]
+[[Category: Turner HL]]
+[[Category: Ward AB]]

9aru

From Proteopedia

Current revision

COVA2-15 fragment antigen binding in complex with SARS-CoV-2 6P-mut7 S protein

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox