7t3m

From Proteopedia

(Difference between revisions)

Revision as of 07:43, 8 March 2023

SARS-CoV-2 S (Spike Glycoprotein) D614G with Three (3) RBDs Up, Bound to Antibody 2-7 scFv, composite map

Structural highlights

7t3m is a 9 chain structure with sequence from Escherichia coli and Severe acute respiratory syndrome coronavirus 2. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
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

Monoclonal antibodies are a promising approach to treat COVID-19, however the emergence of SARS-CoV-2 variants has challenged the efficacy and future of these therapies. Antibody cocktails are being employed to mitigate these challenges, but neutralization escape remains a major challenge and alternative strategies are needed. Here we present two anti-SARS-CoV-2 spike binding antibodies, one Class 1 and one Class 4, selected from our non-immune human single-chain variable fragment (scFv) phage library, that are engineered into four, fully-human IgG-like bispecific antibodies (BsAb). Prophylaxis of hACE2 mice and post-infection treatment of golden hamsters demonstrates the efficacy of the monospecific antibodies against the original Wuhan strain, while promising in vitro results with the BsAbs demonstrate enhanced binding and distinct synergistic effects on neutralizing activity against circulating variants of concern. In particular, one BsAb engineered in a tandem scFv-Fc configuration shows synergistic neutralization activity against several variants of concern including B.1.617.2. This work provides evidence that synergistic neutralization can be achieved using a BsAb scaffold, and serves as a foundation for the future development of broadly reactive BsAbs against emerging variants of concern.

IgG-like bispecific antibodies with potent and synergistic neutralization against circulating SARS-CoV-2 variants of concern.,Chang MR, Tomasovic L, Kuzmina NA, Ronk AJ, Byrne PO, Johnson R, Storm N, Olmedillas E, Hou YJ, Schafer A, Leist SR, Tse LV, Ke H, Coherd C, Nguyen K, Kamkaew M, Honko A, Zhu Q, Alter G, Saphire EO, McLellan JS, Griffiths A, Baric RS, Bukreyev A, Marasco WA Nat Commun. 2022 Oct 3;13(1):5814. doi: 10.1038/s41467-022-33030-4. PMID:36192374^[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
↑ Chang MR, Tomasovic L, Kuzmina NA, Ronk AJ, Byrne PO, Johnson R, Storm N, Olmedillas E, Hou YJ, Schäfer A, Leist SR, Tse LV, Ke H, Coherd C, Nguyen K, Kamkaew M, Honko A, Zhu Q, Alter G, Saphire EO, McLellan JS, Griffiths A, Baric RS, Bukreyev A, Marasco WA. IgG-like bispecific antibodies with potent and synergistic neutralization against circulating SARS-CoV-2 variants of concern. Nat Commun. 2022 Oct 3;13(1):5814. PMID:36192374 doi:10.1038/s41467-022-33030-4

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7t3m"

Categories: Escherichia coli | Large Structures | Severe acute respiratory syndrome coronavirus 2 | Byrne PO | McLellan JS

@@ Line 1: / Line 1: @@
 ==SARS-CoV-2 S (Spike Glycoprotein) D614G with Three (3) RBDs Up, Bound to Antibody 2-7 scFv, composite map==
-<StructureSection load='7t3m' size='340' side='right'caption='[[7t3m]]' scene=''>
+<StructureSection load='7t3m' size='340' side='right'caption='[[7t3m]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7T3M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7T3M FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7t3m]] is a 9 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] 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=7T3M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7T3M 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=7t3m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7t3m OCA], [https://pdbe.org/7t3m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7t3m RCSB], [https://www.ebi.ac.uk/pdbsum/7t3m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7t3m 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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7t3m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7t3m OCA], [https://pdbe.org/7t3m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7t3m RCSB], [https://www.ebi.ac.uk/pdbsum/7t3m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7t3m 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 ==
+Monoclonal antibodies are a promising approach to treat COVID-19, however the emergence of SARS-CoV-2 variants has challenged the efficacy and future of these therapies. Antibody cocktails are being employed to mitigate these challenges, but neutralization escape remains a major challenge and alternative strategies are needed. Here we present two anti-SARS-CoV-2 spike binding antibodies, one Class 1 and one Class 4, selected from our non-immune human single-chain variable fragment (scFv) phage library, that are engineered into four, fully-human IgG-like bispecific antibodies (BsAb). Prophylaxis of hACE2 mice and post-infection treatment of golden hamsters demonstrates the efficacy of the monospecific antibodies against the original Wuhan strain, while promising in vitro results with the BsAbs demonstrate enhanced binding and distinct synergistic effects on neutralizing activity against circulating variants of concern. In particular, one BsAb engineered in a tandem scFv-Fc configuration shows synergistic neutralization activity against several variants of concern including B.1.617.2. This work provides evidence that synergistic neutralization can be achieved using a BsAb scaffold, and serves as a foundation for the future development of broadly reactive BsAbs against emerging variants of concern.
+IgG-like bispecific antibodies with potent and synergistic neutralization against circulating SARS-CoV-2 variants of concern.,Chang MR, Tomasovic L, Kuzmina NA, Ronk AJ, Byrne PO, Johnson R, Storm N, Olmedillas E, Hou YJ, Schafer A, Leist SR, Tse LV, Ke H, Coherd C, Nguyen K, Kamkaew M, Honko A, Zhu Q, Alter G, Saphire EO, McLellan JS, Griffiths A, Baric RS, Bukreyev A, Marasco WA Nat Commun. 2022 Oct 3;13(1):5814. doi: 10.1038/s41467-022-33030-4. PMID:36192374<ref>PMID:36192374</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 7t3m" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Antibody 3D structures|Antibody 3D structures]]
+== References ==
+<references/>
 __TOC__
 </StructureSection>
+[[Category: Escherichia coli]]
 [[Category: Large Structures]]
+[[Category: Severe acute respiratory syndrome coronavirus 2]]
 [[Category: Byrne PO]]
 [[Category: McLellan JS]]

7t3m

From Proteopedia

Revision as of 07:43, 8 March 2023

SARS-CoV-2 S (Spike Glycoprotein) D614G with Three (3) RBDs Up, Bound to Antibody 2-7 scFv, composite map

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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