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| | <StructureSection load='3kpe' size='340' side='right'caption='[[3kpe]], [[Resolution|resolution]] 1.47Å' scene=''> | | <StructureSection load='3kpe' size='340' side='right'caption='[[3kpe]], [[Resolution|resolution]] 1.47Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3kpe]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human_respiratory_syncytial_virus Human respiratory syncytial virus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3KPE OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=3KPE FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3kpe]] is a 2 chain structure with sequence from [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=3KPE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3KPE FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=TM3:2-[[6-[[[2-(3-HYDROXYPROPYL)-5-METHYLPHENYL]AMINO]METHYL]-2-[[3-(4-MORPHOLINYL)PROPYL]AMINO]-1H-BENZIMIDAZOL-1-YL]METHYL]-6-METHYL-3-PYRIDINOL'>TM3</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]] 1.47Å</td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=3kpe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3kpe OCA], [http://pdbe.org/3kpe PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3kpe RCSB], [http://www.ebi.ac.uk/pdbsum/3kpe PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3kpe ProSAT]</span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=TM3:2-[[6-[[[2-(3-HYDROXYPROPYL)-5-METHYLPHENYL]AMINO]METHYL]-2-[[3-(4-MORPHOLINYL)PROPYL]AMINO]-1H-BENZIMIDAZOL-1-YL]METHYL]-6-METHYL-3-PYRIDINOL'>TM3</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=3kpe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3kpe OCA], [https://pdbe.org/3kpe PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3kpe RCSB], [https://www.ebi.ac.uk/pdbsum/3kpe PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3kpe 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> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human respiratory syncytial virus]] | + | [[Category: Human respiratory syncytial virus A2]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Andries, K]] | + | [[Category: Andries K]] |
| - | [[Category: Arnoult, E]] | + | [[Category: Arnoult E]] |
| - | [[Category: Bondt, H De]] | + | [[Category: Cummings MD]] |
| - | [[Category: Cummings, M D]] | + | [[Category: De Bondt H]] |
| - | [[Category: Roymans, D]] | + | [[Category: Roymans D]] |
| - | [[Category: Vlijmen, H Van]] | + | [[Category: Van Vlijmen H]] |
| - | [[Category: Alpha helix]]
| + | |
| - | [[Category: Coiled-coil]]
| + | |
| - | [[Category: Envelope protein]]
| + | |
| - | [[Category: Fusion protein]]
| + | |
| - | [[Category: Glycoprotein]]
| + | |
| - | [[Category: Host cell membrane]]
| + | |
| - | [[Category: Host membrane]]
| + | |
| - | [[Category: Lipoprotein]]
| + | |
| - | [[Category: Membrane]]
| + | |
| - | [[Category: Palmitate]]
| + | |
| - | [[Category: Peptide-small-molecule complex]]
| + | |
| - | [[Category: Transmembrane]]
| + | |
| - | [[Category: Viral protein]]
| + | |
| - | [[Category: Virion]]
| + | |
| 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]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Six-helix bundle (6HB) formation is an essential step for many viruses that rely on a class I fusion protein to enter a target cell and initiate replication. Because the binding modes of small molecule inhibitors of 6HB formation are largely unknown, precisely how they disrupt 6HB formation remains unclear, and structure-based design of improved inhibitors is thus seriously hampered. Here we present the high resolution crystal structure of TMC353121, a potent inhibitor of respiratory syncytial virus (RSV), bound at a hydrophobic pocket of the 6HB formed by amino acid residues from both HR1 and HR2 heptad-repeats. Binding of TMC353121 stabilizes the interaction of HR1 and HR2 in an alternate conformation of the 6HB, in which direct binding interactions are formed between TMC353121 and both HR1 and HR2. Rather than completely preventing 6HB formation, our data indicate that TMC353121 inhibits fusion by causing a local disturbance of the natural 6HB conformation.
Binding of a potent small-molecule inhibitor of six-helix bundle formation requires interactions with both heptad-repeats of the RSV fusion protein.,Roymans D, De Bondt HL, Arnoult E, Geluykens P, Gevers T, Van Ginderen M, Verheyen N, Kim H, Willebrords R, Bonfanti JF, Bruinzeel W, Cummings MD, van Vlijmen H, Andries K Proc Natl Acad Sci U S A. 2009 Dec 4. PMID:19966279[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
- ↑ Roymans D, De Bondt HL, Arnoult E, Geluykens P, Gevers T, Van Ginderen M, Verheyen N, Kim H, Willebrords R, Bonfanti JF, Bruinzeel W, Cummings MD, van Vlijmen H, Andries K. Binding of a potent small-molecule inhibitor of six-helix bundle formation requires interactions with both heptad-repeats of the RSV fusion protein. Proc Natl Acad Sci U S A. 2009 Dec 4. PMID:19966279
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