- EMDB-6077: Characterization of a broadly neutralizing monoclonal antibody th... -
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Open data
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Basic information
Entry
Database: EMDB / ID: EMD-6077
Title
Characterization of a broadly neutralizing monoclonal antibody that targets the fusion domain of group 2 influenza A virus hemagglutinin
Map data
Negative stain reconstruction of Fab 9H10 bound to hemagglutinin (H3) from Influenza A/Hong Kong/1/1968 (H3N2), initiated with common lines, refined with projection matching against single particles, under C3 symmetry
Sample
Sample: Fab 9H10 bound to hemagglutinin (H3) from Influenza A/Hong Kong/1/1968 (H3N2)
Protein or peptide: hemagglutinin
Protein or peptide: Fab of monoclonal antibody 9H10
Keywords
group 2 influenza A virus / broadly neutralizing antibody
Biological species
Influenza A virus / Mus musculus (house mouse)
Method
single particle reconstruction / negative staining / Resolution: 24.6 Å
Journal: J Virol / Year: 2014 Title: Characterization of a broadly neutralizing monoclonal antibody that targets the fusion domain of group 2 influenza A virus hemagglutinin. Authors: Gene S Tan / Peter S Lee / Ryan M B Hoffman / Beryl Mazel-Sanchez / Florian Krammer / Paul E Leon / Andrew B Ward / Ian A Wilson / Peter Palese / Abstract: Due to continuous changes to its antigenic regions, influenza viruses can evade immune detection and cause a significant amount of morbidity and mortality around the world. Influenza vaccinations can ...Due to continuous changes to its antigenic regions, influenza viruses can evade immune detection and cause a significant amount of morbidity and mortality around the world. Influenza vaccinations can protect against disease but must be annually reformulated to match the current circulating strains. In the development of a broad-spectrum influenza vaccine, the elucidation of conserved epitopes is paramount. To this end, we designed an immunization strategy in mice to boost the humoral response against conserved regions of the hemagglutinin (HA) glycoprotein. Of note, generation and identification of broadly neutralizing antibodies that target group 2 HAs are rare and thus far have yielded only a few monoclonal antibodies (MAbs). Here, we demonstrate that mouse MAb 9H10 has broad and potent in vitro neutralizing activity against H3 and H10 group 2 influenza A subtypes. In the mouse model, MAb 9H10 protects mice against two divergent mouse-adapted H3N2 strains, in both pre- and postexposure administration regimens. In vitro and cell-free assays suggest that MAb 9H10 inhibits viral replication by blocking HA-dependent fusion of the viral and endosomal membranes early in the replication cycle and by disrupting viral particle egress in the late stage of infection. Interestingly, electron microscopy reconstructions of MAb 9H10 bound to the HA reveal that it binds a similar binding footprint to MAbs CR8020 and CR8043. IMPORTANCE: The influenza hemagglutinin is the major antigenic target of the humoral immune response. However, due to continuous antigenic changes that occur on the surface of this glycoprotein, ...IMPORTANCE: The influenza hemagglutinin is the major antigenic target of the humoral immune response. However, due to continuous antigenic changes that occur on the surface of this glycoprotein, influenza viruses can escape the immune system and cause significant disease to the host. Toward the development of broad-spectrum therapeutics and vaccines against influenza virus, elucidation of conserved regions of influenza viruses is crucial. Thus, defining these types of epitopes through the generation and characterization of broadly neutralizing monoclonal antibodies (MAbs) can greatly assist others in highlighting conserved regions of hemagglutinin. Here, we demonstrate that MAb 9H10 that targets the hemagglutinin stalk has broadly neutralizing activity against group 2 influenza A viruses in vitro and in vivo.
History
Deposition
Aug 28, 2014
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Header (metadata) release
Sep 24, 2014
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Map release
Sep 24, 2014
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Update
Nov 12, 2014
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Current status
Nov 12, 2014
Processing site: RCSB / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
Download / File: emd_6077.map.gz / Format: CCP4 / Size: 1001 KB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotation
Negative stain reconstruction of Fab 9H10 bound to hemagglutinin (H3) from Influenza A/Hong Kong/1/1968 (H3N2), initiated with common lines, refined with projection matching against single particles, under C3 symmetry
Voxel size
X=Y=Z: 6.15 Å
Density
Contour Level
By AUTHOR: 24.0 / Movie #1: 24
Minimum - Maximum
-23.517362590000001 - 134.20054626000001
Average (Standard dev.)
0.16498315 (±6.23728752)
Symmetry
Space group: 1
Details
EMDB XML:
Map geometry
Axis order
X
Y
Z
Origin
-32
-32
-32
Dimensions
64
64
64
Spacing
64
64
64
Cell
A=B=C: 393.6 Å α=β=γ: 90.0 °
CCP4 map header:
mode
Image stored as Reals
Å/pix. X/Y/Z
6.15
6.15
6.15
M x/y/z
64
64
64
origin x/y/z
0.000
0.000
0.000
length x/y/z
393.600
393.600
393.600
α/β/γ
90.000
90.000
90.000
start NX/NY/NZ
0
0
0
NX/NY/NZ
96
96
80
MAP C/R/S
1
2
3
start NC/NR/NS
-32
-32
-32
NC/NR/NS
64
64
64
D min/max/mean
-23.517
134.201
0.165
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Supplemental data
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Sample components
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Entire : Fab 9H10 bound to hemagglutinin (H3) from Influenza A/Hong Kong/1...
Entire
Name: Fab 9H10 bound to hemagglutinin (H3) from Influenza A/Hong Kong/1/1968 (H3N2)
Components
Sample: Fab 9H10 bound to hemagglutinin (H3) from Influenza A/Hong Kong/1/1968 (H3N2)
Protein or peptide: hemagglutinin
Protein or peptide: Fab of monoclonal antibody 9H10
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Supramolecule #1000: Fab 9H10 bound to hemagglutinin (H3) from Influenza A/Hong Kong/1...
Supramolecule
Name: Fab 9H10 bound to hemagglutinin (H3) from Influenza A/Hong Kong/1/1968 (H3N2) type: sample / ID: 1000 Oligomeric state: one hemagglutinin homotrimer binds to three 9H10 Fabs Number unique components: 2
Model: Tecnai Spirit / Image courtesy: FEI Company
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Image processing
Details
Initial model determined by common lines from reference-free class averages. Final model refined against single particles using projection matching.
Final reconstruction
Algorithm: OTHER / Resolution.type: BY AUTHOR / Resolution: 24.6 Å / Resolution method: OTHER / Software - Name: EMAN2, Sparx / Number images used: 4791
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