7z8o

From Proteopedia

(Difference between revisions)

Revision as of 21:14, 28 June 2023

Crystal structure of SARS-CoV-2 S RBD in complex with a stapled peptide

Structural highlights

7z8o is a 2 chain structure with sequence from Severe acute respiratory syndrome coronavirus 2 and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 0.96Å
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

COVID-19 has stimulated the rapid development of new antibody and small molecule therapeutics to inhibit SARS-CoV-2 infection. Here we describe a third antiviral modality that combines the drug-like advantages of both. Bicycles are entropically constrained peptides stabilized by a central chemical scaffold into a bi-cyclic structure. Rapid screening of diverse bacteriophage libraries against SARS-CoV-2 Spike yielded unique Bicycle binders across the entire protein. Exploiting Bicycles' inherent chemical combinability, we converted early micromolar hits into nanomolar viral inhibitors through simple multimerization. We also show how combining Bicycles against different epitopes into a single biparatopic agent allows Spike from diverse variants of concern (VoC) to be targeted (Alpha, Beta, Delta and Omicron). Finally, we demonstrate in both male hACE2-transgenic mice and Syrian golden hamsters that both multimerized and biparatopic Bicycles reduce viraemia and prevent host inflammation. These results introduce Bicycles as a potential antiviral modality to tackle new and rapidly evolving viruses.

Multivalent bicyclic peptides are an effective antiviral modality that can potently inhibit SARS-CoV-2.,Gaynor KU, Vaysburd M, Harman MAJ, Albecka A, Jeffrey P, Beswick P, Papa G, Chen L, Mallery D, McGuinness B, Van Rietschoten K, Stanway S, Brear P, Lulla A, Ciazynska K, Chang VT, Sharp J, Neary M, Box H, Herriott J, Kijak E, Tatham L, Bentley EG, Sharma P, Kirby A, Han X, Stewart JP, Owen A, Briggs JAG, Hyvonen M, Skynner MJ, James LC Nat Commun. 2023 Jun 16;14(1):3583. doi: 10.1038/s41467-023-39158-1. PMID:37328472^[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
↑ Gaynor KU, Vaysburd M, Harman MAJ, Albecka A, Jeffrey P, Beswick P, Papa G, Chen L, Mallery D, McGuinness B, Van Rietschoten K, Stanway S, Brear P, Lulla A, Ciazynska K, Chang VT, Sharp J, Neary M, Box H, Herriott J, Kijak E, Tatham L, Bentley EG, Sharma P, Kirby A, Han X, Stewart JP, Owen A, Briggs JAG, Hyvönen M, Skynner MJ, James LC. Multivalent bicyclic peptides are an effective antiviral modality that can potently inhibit SARS-CoV-2. Nat Commun. 2023 Jun 16;14(1):3583. PMID:37328472 doi:10.1038/s41467-023-39158-1

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/7z8o"

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 7z8o is ON HOLD  until 2024-09-18
+==Crystal structure of SARS-CoV-2 S RBD in complex with a stapled peptide==
+<StructureSection load='7z8o' size='340' side='right'caption='[[7z8o]], [[Resolution|resolution]] 0.96&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[7z8o]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Severe_acute_respiratory_syndrome_coronavirus_2 Severe acute respiratory syndrome coronavirus 2] 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=7Z8O OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7Z8O FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 0.96&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0JY:4-METHYL-L-LEUCINE'>0JY</scene>, <scene name='pdbligand=4J5:amino{[(3S)-3-amino-3-carboxypropyl]amino}methaniminium'>4J5</scene>, <scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=CY3:2-AMINO-3-MERCAPTO-PROPIONAMIDE'>CY3</scene>, <scene name='pdbligand=DAL:D-ALANINE'>DAL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=KZ0:2,4,6-tris(chloromethyl)-1,3,5-triazine'>KZ0</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=7z8o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7z8o OCA], [https://pdbe.org/7z8o PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7z8o RCSB], [https://www.ebi.ac.uk/pdbsum/7z8o PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7z8o 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 ==
+COVID-19 has stimulated the rapid development of new antibody and small molecule therapeutics to inhibit SARS-CoV-2 infection. Here we describe a third antiviral modality that combines the drug-like advantages of both. Bicycles are entropically constrained peptides stabilized by a central chemical scaffold into a bi-cyclic structure. Rapid screening of diverse bacteriophage libraries against SARS-CoV-2 Spike yielded unique Bicycle binders across the entire protein. Exploiting Bicycles' inherent chemical combinability, we converted early micromolar hits into nanomolar viral inhibitors through simple multimerization. We also show how combining Bicycles against different epitopes into a single biparatopic agent allows Spike from diverse variants of concern (VoC) to be targeted (Alpha, Beta, Delta and Omicron). Finally, we demonstrate in both male hACE2-transgenic mice and Syrian golden hamsters that both multimerized and biparatopic Bicycles reduce viraemia and prevent host inflammation. These results introduce Bicycles as a potential antiviral modality to tackle new and rapidly evolving viruses.
-Authors:
+Multivalent bicyclic peptides are an effective antiviral modality that can potently inhibit SARS-CoV-2.,Gaynor KU, Vaysburd M, Harman MAJ, Albecka A, Jeffrey P, Beswick P, Papa G, Chen L, Mallery D, McGuinness B, Van Rietschoten K, Stanway S, Brear P, Lulla A, Ciazynska K, Chang VT, Sharp J, Neary M, Box H, Herriott J, Kijak E, Tatham L, Bentley EG, Sharma P, Kirby A, Han X, Stewart JP, Owen A, Briggs JAG, Hyvonen M, Skynner MJ, James LC Nat Commun. 2023 Jun 16;14(1):3583. doi: 10.1038/s41467-023-39158-1. PMID:37328472<ref>PMID:37328472</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 7z8o" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Large Structures]]
+[[Category: Severe acute respiratory syndrome coronavirus 2]]
+[[Category: Synthetic construct]]
+[[Category: Brear P]]
+[[Category: Chen L]]
+[[Category: Dods R]]
+[[Category: Gaynor K]]
+[[Category: Harman M]]
+[[Category: Hyvonen M]]

7z8o

From Proteopedia

Revision as of 21:14, 28 June 2023

Crystal structure of SARS-CoV-2 S RBD in complex with a stapled peptide

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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