8czi: Difference between revisions
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The | ==Cryo-EM structure of the SARS-CoV-2 HR1HR2 fusion core complex with extended HR2== | ||
<StructureSection load='8czi' size='340' side='right'caption='[[8czi]], [[Resolution|resolution]] 2.22Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[8czi]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Nostoc_punctiforme_PCC_73102 Nostoc punctiforme PCC 73102] 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=8CZI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8CZI 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]] 2.22Å</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=8czi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8czi OCA], [https://pdbe.org/8czi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8czi RCSB], [https://www.ebi.ac.uk/pdbsum/8czi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8czi ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenge currently available coronavirus disease 2019 vaccines and monoclonal antibody therapies through epitope change on the receptor binding domain of the viral spike glycoprotein. Hence, there is a specific urgent need for alternative antivirals that target processes less likely to be affected by mutation, such as the membrane fusion step of viral entry into the host cell. One such antiviral class includes peptide inhibitors, which block formation of the so-called heptad repeat 1 and 2 (HR1HR2) six-helix bundle of the SARS-CoV-2 spike (S) protein and thus interfere with viral membrane fusion. We performed structural studies of the HR1HR2 bundle, revealing an extended, well-folded N-terminal region of HR2 that interacts with the HR1 triple helix. Based on this structure, we designed an extended HR2 peptide that achieves single-digit nanomolar inhibition of SARS-CoV-2 in cell-based and virus-based assays without the need for modifications such as lipidation or chemical stapling. The peptide also strongly inhibits all major SARS-CoV-2 variants to date. This extended peptide is approximately 100-fold more potent than all previously published short, unmodified HR2 peptides, and it has a very long inhibition lifetime after washout in virus infection assays, suggesting that it targets a prehairpin intermediate of the SARS-CoV-2 S protein. Together, these results suggest that regions outside the HR2 helical region may offer new opportunities for potent peptide-derived therapeutics for SARS-CoV-2 and its variants, and even more distantly related viruses, and provide further support for the prehairpin intermediate of the S protein. | |||
Nanomolar inhibition of SARS-CoV-2 infection by an unmodified peptide targeting the prehairpin intermediate of the spike protein.,Yang K, Wang C, Kreutzberger AJB, Ojha R, Kuivanen S, Couoh-Cardel S, Muratcioglu S, Eisen TJ, White KI, Held RG, Subramanian S, Marcus K, Pfuetzner RA, Esquivies L, Doyle CA, Kuriyan J, Vapalahti O, Balistreri G, Kirchhausen T, Brunger AT Proc Natl Acad Sci U S A. 2022 Oct 4;119(40):e2210990119. doi: , 10.1073/pnas.2210990119. Epub 2022 Sep 19. PMID:36122200<ref>PMID:36122200</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 8czi" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Spike protein 3D structures|Spike protein 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Nostoc punctiforme PCC 73102]] | |||
[[Category: Severe acute respiratory syndrome coronavirus 2]] | |||
[[Category: Brunger AT]] | |||
[[Category: Yang K]] | |||
Latest revision as of 08:19, 12 June 2024
Cryo-EM structure of the SARS-CoV-2 HR1HR2 fusion core complex with extended HR2Cryo-EM structure of the SARS-CoV-2 HR1HR2 fusion core complex with extended HR2
Structural highlights
Publication Abstract from PubMedVariants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenge currently available coronavirus disease 2019 vaccines and monoclonal antibody therapies through epitope change on the receptor binding domain of the viral spike glycoprotein. Hence, there is a specific urgent need for alternative antivirals that target processes less likely to be affected by mutation, such as the membrane fusion step of viral entry into the host cell. One such antiviral class includes peptide inhibitors, which block formation of the so-called heptad repeat 1 and 2 (HR1HR2) six-helix bundle of the SARS-CoV-2 spike (S) protein and thus interfere with viral membrane fusion. We performed structural studies of the HR1HR2 bundle, revealing an extended, well-folded N-terminal region of HR2 that interacts with the HR1 triple helix. Based on this structure, we designed an extended HR2 peptide that achieves single-digit nanomolar inhibition of SARS-CoV-2 in cell-based and virus-based assays without the need for modifications such as lipidation or chemical stapling. The peptide also strongly inhibits all major SARS-CoV-2 variants to date. This extended peptide is approximately 100-fold more potent than all previously published short, unmodified HR2 peptides, and it has a very long inhibition lifetime after washout in virus infection assays, suggesting that it targets a prehairpin intermediate of the SARS-CoV-2 S protein. Together, these results suggest that regions outside the HR2 helical region may offer new opportunities for potent peptide-derived therapeutics for SARS-CoV-2 and its variants, and even more distantly related viruses, and provide further support for the prehairpin intermediate of the S protein. Nanomolar inhibition of SARS-CoV-2 infection by an unmodified peptide targeting the prehairpin intermediate of the spike protein.,Yang K, Wang C, Kreutzberger AJB, Ojha R, Kuivanen S, Couoh-Cardel S, Muratcioglu S, Eisen TJ, White KI, Held RG, Subramanian S, Marcus K, Pfuetzner RA, Esquivies L, Doyle CA, Kuriyan J, Vapalahti O, Balistreri G, Kirchhausen T, Brunger AT Proc Natl Acad Sci U S A. 2022 Oct 4;119(40):e2210990119. doi: , 10.1073/pnas.2210990119. Epub 2022 Sep 19. PMID:36122200[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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