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| | <StructureSection load='6dc5' size='340' side='right'caption='[[6dc5]], [[Resolution|resolution]] 3.50Å' scene=''> | | <StructureSection load='6dc5' size='340' side='right'caption='[[6dc5]], [[Resolution|resolution]] 3.50Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6dc5]] is a 9 chain structure with sequence from [http://en.wikipedia.org/wiki/Hrsva Hrsva] and [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6DC5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6DC5 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6dc5]] is a 9 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens], [https://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1] and [https://en.wikipedia.org/wiki/Human_respiratory_syncytial_virus_A2 Human respiratory syncytial virus A2]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6DC5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6DC5 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CD:CADMIUM+ION'>CD</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.5Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">IGH@ ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CD:CADMIUM+ION'>CD</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6dc5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dc5 OCA], [http://pdbe.org/6dc5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6dc5 RCSB], [http://www.ebi.ac.uk/pdbsum/6dc5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6dc5 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=6dc5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dc5 OCA], [https://pdbe.org/6dc5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6dc5 RCSB], [https://www.ebi.ac.uk/pdbsum/6dc5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6dc5 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/FUS_HRSVA FUS_HRSVA]] Class I viral fusion protein. Under the current model, the protein has at least 3 conformational states: pre-fusion native state, pre-hairpin intermediate state, and post-fusion hairpin state. During viral and plasma cell membrane fusion, the heptad repeat (HR) regions 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 plasma cell membranes. Directs fusion of viral and cellular membranes leading to delivery of the nucleocapsid into the cytoplasm. This fusion is pH independent and occurs directly at the outer cell membrane. The trimer of F1-F2 (protein F) interacts with glycoprotein G at the virion surface. Upon binding of G to heparan sulfate, the hydrophobic fusion peptide is unmasked and interacts with the cellular membrane, inducing the fusion between host cell and virion membranes. Notably, RSV fusion protein is able to interact directly with heparan sulfate and therefore actively participates in virus attachment. Furthermore, the F2 subunit was identifed as the major determinant of RSV host cell specificity. Later in infection, proteins F expressed at the plasma membrane of infected cells mediate fusion with adjacent cells to form syncytia, a cytopathic effect that could lead to tissue necrosis. The fusion protein is also able to trigger p53-dependent apoptosis.<ref>PMID:12663767</ref> <ref>PMID:18216092</ref> | + | [https://www.uniprot.org/uniprot/FUS_HRSVA FUS_HRSVA] Class I viral fusion protein. Under the current model, the protein has at least 3 conformational states: pre-fusion native state, pre-hairpin intermediate state, and post-fusion hairpin state. During viral and plasma cell membrane fusion, the heptad repeat (HR) regions 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 plasma cell membranes. Directs fusion of viral and cellular membranes leading to delivery of the nucleocapsid into the cytoplasm. This fusion is pH independent and occurs directly at the outer cell membrane. The trimer of F1-F2 (protein F) interacts with glycoprotein G at the virion surface. Upon binding of G to heparan sulfate, the hydrophobic fusion peptide is unmasked and interacts with the cellular membrane, inducing the fusion between host cell and virion membranes. Notably, RSV fusion protein is able to interact directly with heparan sulfate and therefore actively participates in virus attachment. Furthermore, the F2 subunit was identifed as the major determinant of RSV host cell specificity. Later in infection, proteins F expressed at the plasma membrane of infected cells mediate fusion with adjacent cells to form syncytia, a cytopathic effect that could lead to tissue necrosis. The fusion protein is also able to trigger p53-dependent apoptosis.<ref>PMID:12663767</ref> <ref>PMID:18216092</ref> [https://www.uniprot.org/uniprot/M1E1E4_9HIV1 M1E1E4_9HIV1] |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Hrsva]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]] | + | [[Category: Human immunodeficiency virus 1]] |
| | + | [[Category: Human respiratory syncytial virus A2]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Jones, H G]] | + | [[Category: Jones HG]] |
| - | [[Category: McLellan, J S]] | + | [[Category: McLellan JS]] |
| - | [[Category: Human antibody]]
| + | |
| - | [[Category: Immune system]]
| + | |
| - | [[Category: Viral fusion glycoprotein]]
| + | |
| Structural highlights
Function
FUS_HRSVA Class I viral fusion protein. Under the current model, the protein has at least 3 conformational states: pre-fusion native state, pre-hairpin intermediate state, and post-fusion hairpin state. During viral and plasma cell membrane fusion, the heptad repeat (HR) regions 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 plasma cell membranes. Directs fusion of viral and cellular membranes leading to delivery of the nucleocapsid into the cytoplasm. This fusion is pH independent and occurs directly at the outer cell membrane. The trimer of F1-F2 (protein F) interacts with glycoprotein G at the virion surface. Upon binding of G to heparan sulfate, the hydrophobic fusion peptide is unmasked and interacts with the cellular membrane, inducing the fusion between host cell and virion membranes. Notably, RSV fusion protein is able to interact directly with heparan sulfate and therefore actively participates in virus attachment. Furthermore, the F2 subunit was identifed as the major determinant of RSV host cell specificity. Later in infection, proteins F expressed at the plasma membrane of infected cells mediate fusion with adjacent cells to form syncytia, a cytopathic effect that could lead to tissue necrosis. The fusion protein is also able to trigger p53-dependent apoptosis.[1] [2] M1E1E4_9HIV1
Publication Abstract from PubMed
The respiratory syncytial virus (RSV) fusion (F) glycoprotein is a major target of neutralizing antibodies arising from natural infection, and antibodies that specifically bind to the prefusion conformation of RSV F generally demonstrate the greatest neutralization potency. Prefusion-stabilized RSV F variants have been engineered as vaccine antigens, but crystal structures of these variants have revealed conformational differences in a key antigenic site located at the apex of the trimer, referred to as antigenic site O. Currently, it is unclear if flexibility in this region is an inherent property of prefusion RSV F or if it is related to inadequate stabilization of site O in the engineered variants. Therefore, we set out to investigate the conformational flexibility of antigenic site O, as well as the ability of the human immune system to recognize alternative conformations of this site, by determining crystal structures of prefusion RSV F bound to neutralizing human-derived antibodies AM22 and RSD5. Both antibodies bound with high affinity and were specific for the prefusion conformation of RSV F. Crystal structures of the complexes revealed that the antibodies recognized distinct conformations of antigenic site O, each diverging at a conserved proline residue located in the middle of an alpha-helix. These data suggest that antigenic site O exists as an ensemble of conformations, with individual antibodies recognizing discrete states. Collectively, these results have implications for the refolding of pneumovirus and paramyxovirus fusion proteins and should inform development of prefusion-stabilized RSV F vaccine candidates.
Alternative conformations of a major antigenic site on RSV F.,Jones HG, Battles MB, Lin CC, Bianchi S, Corti D, McLellan JS PLoS Pathog. 2019 Jul 15;15(7):e1007944. doi: 10.1371/journal.ppat.1007944., eCollection 2019 Jul. PMID:31306469[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Schlender J, Zimmer G, Herrler G, Conzelmann KK. Respiratory syncytial virus (RSV) fusion protein subunit F2, not attachment protein G, determines the specificity of RSV infection. J Virol. 2003 Apr;77(8):4609-16. PMID:12663767
- ↑ Eckardt-Michel J, Lorek M, Baxmann D, Grunwald T, Keil GM, Zimmer G. The fusion protein of respiratory syncytial virus triggers p53-dependent apoptosis. J Virol. 2008 Apr;82(7):3236-49. Epub 2008 Jan 23. PMID:18216092 doi:JVI.01887-07
- ↑ Jones HG, Battles MB, Lin CC, Bianchi S, Corti D, McLellan JS. Alternative conformations of a major antigenic site on RSV F. PLoS Pathog. 2019 Jul 15;15(7):e1007944. doi: 10.1371/journal.ppat.1007944., eCollection 2019 Jul. PMID:31306469 doi:http://dx.doi.org/10.1371/journal.ppat.1007944
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