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5ea4

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Revision as of 06:50, 22 April 2020

Crystal Structure of Inhibitor JNJ-49153390 in Complex with Prefusion RSV F Glycoprotein

Structural highlights

5ea4 is a 1 chain structure with sequence from Hrsva. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Related:	4mmu, 5ea3, 5ea5, 5ea7, 5ea6, 5ea8
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

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^[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
↑ 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. Molecular mechanism of respiratory syncytial virus fusion inhibitors. Nat Chem Biol. 2015 Dec 7. doi: 10.1038/nchembio.1982. PMID:26641933 doi:http://dx.doi.org/10.1038/nchembio.1982

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5ea4"

@@ Line 1: / Line 1: @@
 ==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 ==
-<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 [http://en.wikipedia.org/wiki/Hrsva Hrsva]. 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://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='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='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='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'>[http://proteopedia.org/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], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ea4 ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 22: / Line 23: @@
 __TOC__
 </StructureSection>
+[[Category: Hrsva]]
+[[Category: Large Structures]]
 [[Category: Arnoult, E]]
 [[Category: Battles, M B]]

5ea4

From Proteopedia

Revision as of 06:50, 22 April 2020

Crystal Structure of Inhibitor JNJ-49153390 in Complex with Prefusion RSV F Glycoprotein

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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