8dlk: Difference between revisions
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[8dlk]] is a 2 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=8DLK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8DLK FirstGlance]. <br> | <table><tr><td colspan='2'>[[8dlk]] is a 2 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=8DLK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8DLK FirstGlance]. <br> | ||
</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> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.04Å</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=8dlk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8dlk OCA], [https://pdbe.org/8dlk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8dlk RCSB], [https://www.ebi.ac.uk/pdbsum/8dlk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8dlk ProSAT]</span></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=8dlk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8dlk OCA], [https://pdbe.org/8dlk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8dlk RCSB], [https://www.ebi.ac.uk/pdbsum/8dlk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8dlk ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == 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;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
Mutations in the spike glycoproteins of SARS-CoV-2 variants of concern have independently been shown to enhance aspects of spike protein fitness. Here, we describe an antibody fragment ( | Mutations in the spike glycoproteins of SARS-CoV-2 variants of concern have independently been shown to enhance aspects of spike protein fitness. Here, we describe an antibody fragment (V(H) ab6) that neutralizes all major variants including the recently emerged BA.1 and BA.2 Omicron subvariants, with a unique mode of binding revealed by cryo-EM studies. Further, we provide a comparative analysis of the mutational effects within previously emerged variant spikes and identify the structural role of mutations within the NTD and RBD in evading antibody neutralization. Our analysis shows that the highly mutated Gamma N-terminal domain exhibits considerable structural rearrangements, partially explaining its decreased neutralization by convalescent sera. Our results provide mechanistic insights into the structural, functional, and antigenic consequences of SARS-CoV-2 spike mutations and highlight a spike protein vulnerability that may be exploited to achieve broad protection against circulating variants. | ||
SARS-CoV-2 variants of concern: spike protein mutational analysis and epitope for broad neutralization.,Mannar D, Saville JW, Sun Z, Zhu X, Marti MM, Srivastava SS, Berezuk AM, Zhou S, Tuttle KS, Sobolewski MD, Kim A, Treat BR, Da Silva Castanha PM, Jacobs JL, Barratt-Boyes SM, Mellors JW, Dimitrov DS, Li W, Subramaniam S Nat Commun. 2022 Aug 18;13(1):4696. doi: 10.1038/s41467-022-32262-8. PMID:35982054<ref>PMID:35982054</ref> | SARS-CoV-2 variants of concern: spike protein mutational analysis and epitope for broad neutralization.,Mannar D, Saville JW, Sun Z, Zhu X, Marti MM, Srivastava SS, Berezuk AM, Zhou S, Tuttle KS, Sobolewski MD, Kim A, Treat BR, Da Silva Castanha PM, Jacobs JL, Barratt-Boyes SM, Mellors JW, Dimitrov DS, Li W, Subramaniam S Nat Commun. 2022 Aug 18;13(1):4696. doi: 10.1038/s41467-022-32262-8. PMID:35982054<ref>PMID:35982054</ref> | ||
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</div> | </div> | ||
<div class="pdbe-citations 8dlk" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 8dlk" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Spike protein 3D structures|Spike protein 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
Latest revision as of 17:29, 6 November 2024
Cryo-EM structure of SARS-CoV-2 Alpha (B.1.1.7) spike protein in complex with human ACE2 (focused refinement of RBD and ACE2)Cryo-EM structure of SARS-CoV-2 Alpha (B.1.1.7) spike protein in complex with human ACE2 (focused refinement of RBD and ACE2)
Structural highlights
FunctionSPIKE_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 PubMedMutations in the spike glycoproteins of SARS-CoV-2 variants of concern have independently been shown to enhance aspects of spike protein fitness. Here, we describe an antibody fragment (V(H) ab6) that neutralizes all major variants including the recently emerged BA.1 and BA.2 Omicron subvariants, with a unique mode of binding revealed by cryo-EM studies. Further, we provide a comparative analysis of the mutational effects within previously emerged variant spikes and identify the structural role of mutations within the NTD and RBD in evading antibody neutralization. Our analysis shows that the highly mutated Gamma N-terminal domain exhibits considerable structural rearrangements, partially explaining its decreased neutralization by convalescent sera. Our results provide mechanistic insights into the structural, functional, and antigenic consequences of SARS-CoV-2 spike mutations and highlight a spike protein vulnerability that may be exploited to achieve broad protection against circulating variants. SARS-CoV-2 variants of concern: spike protein mutational analysis and epitope for broad neutralization.,Mannar D, Saville JW, Sun Z, Zhu X, Marti MM, Srivastava SS, Berezuk AM, Zhou S, Tuttle KS, Sobolewski MD, Kim A, Treat BR, Da Silva Castanha PM, Jacobs JL, Barratt-Boyes SM, Mellors JW, Dimitrov DS, Li W, Subramaniam S Nat Commun. 2022 Aug 18;13(1):4696. doi: 10.1038/s41467-022-32262-8. PMID:35982054[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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