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==Crystal Structure of Inhibitor JNJ-49153390 in Complex with Prefusion RSV F Glycoprotein==
==Crystal Structure of Inhibitor JNJ-49153390 in Complex with Prefusion RSV F Glycoprotein==
<StructureSection load='5ea4' size='340' side='right' caption='[[5ea4]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
<StructureSection load='5ea4' size='340' side='right'caption='[[5ea4]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[5ea4]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5EA4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5EA4 FirstGlance]. <br>
<table><tr><td colspan='2'>[[5ea4]] is a 1 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=5EA4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5EA4 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5NM:3-[[5-BROMANYL-1-(3-METHYLSULFONYLPROPYL)BENZIMIDAZOL-2-YL]METHYL]-1-CYCLOPROPYL-IMIDAZO[4,5-C]PYRIDIN-2-ONE'>5NM</scene>, <scene name='pdbligand=NHE:2-[N-CYCLOHEXYLAMINO]ETHANE+SULFONIC+ACID'>NHE</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 2.3&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4mmu|4mmu]], [[5ea3|5ea3]], [[5ea5|5ea5]], [[5ea7|5ea7]], [[5ea6|5ea6]], [[5ea8|5ea8]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5NM:3-[[5-BROMANYL-1-(3-METHYLSULFONYLPROPYL)BENZIMIDAZOL-2-YL]METHYL]-1-CYCLOPROPYL-IMIDAZO[4,5-C]PYRIDIN-2-ONE'>5NM</scene>, <scene name='pdbligand=NHE:2-[N-CYCLOHEXYLAMINO]ETHANE+SULFONIC+ACID'>NHE</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=5ea4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ea4 OCA], [http://pdbe.org/5ea4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ea4 RCSB], [http://www.ebi.ac.uk/pdbsum/5ea4 PDBsum]</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=5ea4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ea4 OCA], [https://pdbe.org/5ea4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ea4 RCSB], [https://www.ebi.ac.uk/pdbsum/5ea4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ea4 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;">
== Publication Abstract from PubMed ==
Respiratory syncytial virus (RSV) is a leading cause of pneumonia and bronchiolitis in young children and the elderly. Therapeutic small molecules have been developed that bind the RSV F glycoprotein and inhibit membrane fusion, yet their binding sites and molecular mechanisms of action remain largely unknown. Here we show that these inhibitors bind to a three-fold-symmetric pocket within the central cavity of the metastable prefusion conformation of RSV F. Inhibitor binding stabilizes this conformation by tethering two regions that must undergo a structural rearrangement to facilitate membrane fusion. Inhibitor-escape mutations occur in residues that directly contact the inhibitors or are involved in the conformational rearrangements required to accommodate inhibitor binding. Resistant viruses do not propagate as well as wild-type RSV in vitro, indicating a fitness cost for inhibitor escape. Collectively, these findings provide new insight into class I viral fusion proteins and should facilitate development of optimal RSV fusion inhibitors.
 
Molecular mechanism of respiratory syncytial virus fusion inhibitors.,Battles MB, Langedijk JP, Furmanova-Hollenstein P, Chaiwatpongsakorn S, Costello HM, Kwanten L, Vranckx L, Vink P, Jaensch S, Jonckers TH, Koul A, Arnoult E, Peeples ME, Roymans D, McLellan JS Nat Chem Biol. 2015 Dec 7. doi: 10.1038/nchembio.1982. PMID:26641933<ref>PMID:26641933</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5ea4" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Arnoult, E]]
[[Category: Human respiratory syncytial virus A2]]
[[Category: Battles, M B]]
[[Category: Large Structures]]
[[Category: Langedijk, J P]]
[[Category: Arnoult E]]
[[Category: McLellan, J S]]
[[Category: Battles MB]]
[[Category: Roymans, D]]
[[Category: Langedijk JP]]
[[Category: Cell invasion-inhibitor complex]]
[[Category: McLellan JS]]
[[Category: Class i viral fusion protein]]
[[Category: Roymans D]]
[[Category: Fusion]]
[[Category: Fusion inhibitor]]
[[Category: Prefusion]]
[[Category: Respiratory syncytial virus]]
[[Category: Viral protein]]

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