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5udc

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Revision as of 12:33, 23 September 2020

Crystal Structure of RSV F A2 Bound to MEDI8897

Structural highlights

5udc is a 9 chain structure with sequence from Hrsva and Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , ,
Related:	5udd, 5ude
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

Prevention of respiratory syncytial virus (RSV) illness in all infants is a major public health priority. However, no vaccine is currently available to protect this vulnerable population. Palivizumab, the only approved agent for RSV prophylaxis, is limited to high-risk infants, and the cost associated with the requirement for dosing throughout the RSV season makes its use impractical for all infants. We describe the development of a monoclonal antibody as potential RSV prophylaxis for all infants with a single intramuscular dose. MEDI8897*, a highly potent human antibody, was optimized from antibody D25, which targets the prefusion conformation of the RSV fusion (F) protein. Crystallographic analysis of Fab in complex with RSV F from subtypes A and B reveals that MEDI8897* binds a highly conserved epitope. MEDI8897* neutralizes a diverse panel of RSV A and B strains with >50-fold higher activity than palivizumab. At similar serum concentrations, prophylactic administration of MEDI8897* was ninefold more potent than palivizumab at reducing pulmonary viral loads by >3 logs in cotton rats infected with either RSV A or B subtypes. MEDI8897 was generated by the introduction of triple amino acid substitutions (YTE) into the Fc domain of MEDI8897*, which led to more than threefold increased half-life in cynomolgus monkeys compared to non-YTE antibody. Considering the pharmacokinetics of palivizumab in infants, which necessitates five monthly doses for protection during an RSV season, the high potency and extended half-life of MEDI8897 support its development as a cost-effective option to protect all infants from RSV disease with once-per-RSV-season dosing in the clinic.

A highly potent extended half-life antibody as a potential RSV vaccine surrogate for all infants.,Zhu Q, McLellan JS, Kallewaard NL, Ulbrandt ND, Palaszynski S, Zhang J, Moldt B, Khan A, Svabek C, McAuliffe JM, Wrapp D, Patel NK, Cook KE, Richter BWM, Ryan PC, Yuan AQ, Suzich JA Sci Transl Med. 2017 May 3;9(388). pii: eaaj1928. doi:, 10.1126/scitranslmed.aaj1928. PMID:28469033^[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
↑ Zhu Q, McLellan JS, Kallewaard NL, Ulbrandt ND, Palaszynski S, Zhang J, Moldt B, Khan A, Svabek C, McAuliffe JM, Wrapp D, Patel NK, Cook KE, Richter BWM, Ryan PC, Yuan AQ, Suzich JA. A highly potent extended half-life antibody as a potential RSV vaccine surrogate for all infants. Sci Transl Med. 2017 May 3;9(388). pii: eaaj1928. doi:, 10.1126/scitranslmed.aaj1928. PMID:28469033 doi:http://dx.doi.org/10.1126/scitranslmed.aaj1928

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/5udc"

@@ Line 1: / Line 1: @@
 ==Crystal Structure of RSV F A2 Bound to MEDI8897==
-<StructureSection load='5udc' size='340' side='right' caption='[[5udc]], [[Resolution|resolution]] 3.45&Aring;' scene=''>
+<StructureSection load='5udc' size='340' side='right'caption='[[5udc]], [[Resolution|resolution]] 3.45&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5udc]] is a 9 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UDC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5UDC FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5udc]] is a 9 chain structure with sequence from [http://en.wikipedia.org/wiki/Hrsva Hrsva] and [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UDC OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5UDC FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5udd|5udd]], [[5ude|5ude]]</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=5udc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5udc OCA], [http://pdbe.org/5udc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5udc RCSB], [http://www.ebi.ac.uk/pdbsum/5udc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5udc 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=5udc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5udc OCA], [http://pdbe.org/5udc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5udc RCSB], [http://www.ebi.ac.uk/pdbsum/5udc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5udc ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 23: / Line 23: @@
 __TOC__
 </StructureSection>
+[[Category: Hrsva]]
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: McLellan, J S]]
 [[Category: Antibody]]

5udc

From Proteopedia

Revision as of 12:33, 23 September 2020

Crystal Structure of RSV F A2 Bound to MEDI8897

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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