5j3d

From Proteopedia

(Difference between revisions)

Revision as of 07:27, 10 June 2020

Crystal structure of human Fab 14N4 in complex with post-fusion RSV F

Structural highlights

5j3d is a 12 chain structure with sequence from Human and Respiratory syncytial virus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Related:	5itb
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

Palivizumab was the first antiviral monoclonal antibody (mAb) approved for therapeutic use in humans, and remains a prophylactic treatment for infants at risk for severe disease because of respiratory syncytial virus (RSV). Palivizumab is an engineered humanized version of a murine mAb targeting antigenic site II of the RSV fusion (F) protein, a key target in vaccine development. There are limited reported naturally occurring human mAbs to site II; therefore, the structural basis for human antibody recognition of this major antigenic site is poorly understood. Here, we describe a nonneutralizing class of site II-specific mAbs that competed for binding with palivizumab to postfusion RSV F protein. We also describe two classes of site II-specific neutralizing mAbs, one of which escaped competition with nonneutralizing mAbs. An X-ray crystal structure of the neutralizing mAb 14N4 in complex with F protein showed that the binding angle at which human neutralizing mAbs interact with antigenic site II determines whether or not nonneutralizing antibodies compete with their binding. Fine-mapping studies determined that nonneutralizing mAbs that interfere with binding of neutralizing mAbs recognize site II with a pose that facilitates binding to an epitope containing F surface residues on a neighboring protomer. Neutralizing antibodies, like motavizumab and a new mAb designated 3J20 that escape interference by the inhibiting mAbs, avoid such contact by binding at an angle that is shifted away from the nonneutralizing site. Furthermore, binding to rationally and computationally designed site II helix-loop-helix epitope-scaffold vaccines distinguished neutralizing from nonneutralizing site II antibodies.

Structural basis for nonneutralizing antibody competition at antigenic site II of the respiratory syncytial virus fusion protein.,Mousa JJ, Sauer MF, Sevy AM, Finn JA, Bates JT, Alvarado G, King HG, Loerinc LB, Fong RH, Doranz BJ, Correia BE, Kalyuzhniy O, Wen X, Jardetzky TS, Schief WR, Ohi MD, Meiler J, Crowe JE Jr Proc Natl Acad Sci U S A. 2016 Nov 1;113(44):E6849-E6858. Epub 2016 Oct 17. PMID:27791117^[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
↑ Mousa JJ, Sauer MF, Sevy AM, Finn JA, Bates JT, Alvarado G, King HG, Loerinc LB, Fong RH, Doranz BJ, Correia BE, Kalyuzhniy O, Wen X, Jardetzky TS, Schief WR, Ohi MD, Meiler J, Crowe JE Jr. Structural basis for nonneutralizing antibody competition at antigenic site II of the respiratory syncytial virus fusion protein. Proc Natl Acad Sci U S A. 2016 Nov 1;113(44):E6849-E6858. Epub 2016 Oct 17. PMID:27791117 doi:http://dx.doi.org/10.1073/pnas.1609449113

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/5j3d"

@@ Line 1: / Line 1: @@
 ==Crystal structure of human Fab 14N4 in complex with post-fusion RSV F==
-<StructureSection load='5j3d' size='340' side='right' caption='[[5j3d]], [[Resolution|resolution]] 4.08&Aring;' scene=''>
+<StructureSection load='5j3d' size='340' side='right'caption='[[5j3d]], [[Resolution|resolution]] 4.08&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5j3d]] is a 12 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5J3D OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5J3D FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5j3d]] is a 12 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human] and [http://en.wikipedia.org/wiki/Respiratory_syncytial_virus Respiratory syncytial virus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5J3D OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5J3D FirstGlance]. <br>
 </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5itb|5itb]]</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=5j3d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5j3d OCA], [http://pdbe.org/5j3d PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5j3d RCSB], [http://www.ebi.ac.uk/pdbsum/5j3d PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5j3d ProSAT]</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=5j3d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5j3d OCA], [http://pdbe.org/5j3d PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5j3d RCSB], [http://www.ebi.ac.uk/pdbsum/5j3d PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5j3d ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 22: / Line 22: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
+[[Category: Large Structures]]
+[[Category: Respiratory syncytial virus]]
 [[Category: Crowe, J E]]
 [[Category: Mousa, J J]]

5j3d

From Proteopedia

Revision as of 07:27, 10 June 2020

Crystal structure of human Fab 14N4 in complex with post-fusion RSV F

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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