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| | ==Crystal Structure of Respiratory Syncytial Virus Fusion Glycoprotein Stabilized in the Prefusion Conformation by Human Antibody D25== | | ==Crystal Structure of Respiratory Syncytial Virus Fusion Glycoprotein Stabilized in the Prefusion Conformation by Human Antibody D25== |
| - | <StructureSection load='4jhw' size='340' side='right' caption='[[4jhw]], [[Resolution|resolution]] 3.60Å' scene=''> | + | <StructureSection load='4jhw' size='340' side='right'caption='[[4jhw]], [[Resolution|resolution]] 3.60Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4jhw]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Hrsva Hrsva] and [http://en.wikipedia.org/wiki/Human Human]. The February 2014 RCSB PDB [http://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/index.html Molecule of the Month] feature on ''Broadly Neutralizing Antibodies'' by David Goodsell is [http://dx.doi.org/10.2210/rcsb_pdb/mom_2014_2 10.2210/rcsb_pdb/mom_2014_2]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4JHW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4JHW FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4jhw]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Human_respiratory_syncytial_virus_A2 Human respiratory syncytial virus A2]. The February 2014 RCSB PDB [https://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/index.html Molecule of the Month] feature on ''Broadly Neutralizing Antibodies'' by David Goodsell is [https://dx.doi.org/10.2210/rcsb_pdb/mom_2014_2 10.2210/rcsb_pdb/mom_2014_2]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4JHW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4JHW FirstGlance]. <br> |
| - | </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4jha|4jha]]</td></tr> | + | </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=4jhw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jhw OCA], [https://pdbe.org/4jhw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4jhw RCSB], [https://www.ebi.ac.uk/pdbsum/4jhw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4jhw ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">F, fusion glycoprotein ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11259 HRSVA])</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=4jhw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jhw OCA], [http://pdbe.org/4jhw PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4jhw RCSB], [http://www.ebi.ac.uk/pdbsum/4jhw PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4jhw 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> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Broadly Neutralizing Antibodies]] | | [[Category: Broadly Neutralizing Antibodies]] |
| - | [[Category: Hrsva]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]] | + | [[Category: Human respiratory syncytial virus A2]] |
| | + | [[Category: Large Structures]] |
| | [[Category: RCSB PDB Molecule of the Month]] | | [[Category: RCSB PDB Molecule of the Month]] |
| - | [[Category: Baxa, U]] | + | [[Category: Baxa U]] |
| - | [[Category: Beaumont, T]] | + | [[Category: Beaumont T]] |
| - | [[Category: Chen, M]] | + | [[Category: Chen M]] |
| - | [[Category: Du, X]] | + | [[Category: Du X]] |
| - | [[Category: Graepel, K W]] | + | [[Category: Graepel KW]] |
| - | [[Category: Graham, B S]] | + | [[Category: Graham BS]] |
| - | [[Category: Kumar, A]] | + | [[Category: Kumar A]] |
| - | [[Category: Kwong, P D]] | + | [[Category: Kwong PD]] |
| - | [[Category: Leung, S]] | + | [[Category: Leung S]] |
| - | [[Category: Mclellan, J S]] | + | [[Category: Mclellan JS]] |
| - | [[Category: Modjarrad, K]] | + | [[Category: Modjarrad K]] |
| - | [[Category: Xia, N]] | + | [[Category: Xia N]] |
| - | [[Category: Yang, Y]] | + | [[Category: Yang Y]] |
| - | [[Category: Yasuda, E]] | + | [[Category: Yasuda E]] |
| - | [[Category: Zhao, M]] | + | [[Category: Zhao M]] |
| - | [[Category: Zheng, Z]] | + | [[Category: Zheng Z]] |
| - | [[Category: Zhou, T]] | + | [[Category: Zhou T]] |
| - | [[Category: Immune system]]
| + | |
| - | [[Category: Immunoglobulin]]
| + | |
| - | [[Category: Membrane fusion]]
| + | |
| - | [[Category: Type i fusion protein]]
| + | |
| 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]
Publication Abstract from PubMed
The prefusion state of respiratory syncytial virus (RSV) fusion (F) glycoprotein is the target of most RSV-neutralizing activity in human sera, but its metastability has hindered characterization. To overcome this obstacle, we identified prefusion-specific antibodies that were substantially more potent than the prophylactic antibody palivizumab. The cocrystal structure for one of these antibodies, D25, in complex with the F glycoprotein revealed D25 to lock F in its prefusion state by binding to a quaternary epitope at the trimer apex. Electron microscopy showed that two other antibodies, AM22 and 5C4, also bound to the newly identified site of vulnerability, which we named antigenic site O. These studies should enable design of improved vaccine antigens and define new targets for passive prevention of RSV-induced disease.
Structure of RSV fusion glycoprotein trimer bound to a prefusion-specific neutralizing antibody.,McLellan JS, Chen M, Leung S, Graepel KW, Du X, Yang Y, Zhou T, Baxa U, Yasuda E, Beaumont T, Kumar A, Modjarrad K, Zheng Z, Zhao M, Xia N, Kwong PD, Graham BS Science. 2013 May 31;340(6136):1113-7. doi: 10.1126/science.1234914. Epub 2013, Apr 25. PMID:23618766[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
- ↑ McLellan JS, Chen M, Leung S, Graepel KW, Du X, Yang Y, Zhou T, Baxa U, Yasuda E, Beaumont T, Kumar A, Modjarrad K, Zheng Z, Zhao M, Xia N, Kwong PD, Graham BS. Structure of RSV fusion glycoprotein trimer bound to a prefusion-specific neutralizing antibody. Science. 2013 May 31;340(6136):1113-7. doi: 10.1126/science.1234914. Epub 2013, Apr 25. PMID:23618766 doi:10.1126/science.1234914
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