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- EMDB-23792: CryoEM structure of monoclonal Fab 045-09 2B05 binding the latera... -

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Basic information

Entry
Database: EMDB / ID: EMD-23792
TitleCryoEM structure of monoclonal Fab 045-09 2B05 binding the lateral patch of influenza virus H1 HA
Map dataCryoEM map of monoclonal Fab 045-09 2B05 binding the lateral patch of H1 HA
Sample
  • Complex: CryoEM structure of monoclonal Fab 045-09 2B05 binding the lateral patch of H1 HA
    • Complex: monoclonal Fab 045-09 2B05
      • Protein or peptide: Light chain of monoclonal antibody 045-09 2B05
      • Protein or peptide: Heavy chain of monoclonal antibody 045-09 2B05
    • Complex: Hemagglutinin
      • Protein or peptide: Hemagglutinin HA1 chain
      • Protein or peptide: Hemagglutinin HA2 chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Function / homology
Function and homology information


viral budding from plasma membrane / clathrin-dependent endocytosis of virus by host cell / host cell surface receptor binding / apical plasma membrane / fusion of virus membrane with host plasma membrane / fusion of virus membrane with host endosome membrane / viral envelope / virion attachment to host cell / host cell plasma membrane / virion membrane
Similarity search - Function
Haemagglutinin, influenzavirus A / Haemagglutinin, HA1 chain, alpha/beta domain superfamily / Haemagglutinin / Haemagglutinin, influenzavirus A/B / Viral capsid/haemagglutinin protein
Similarity search - Domain/homology
Biological speciesHomo sapiens (human) / Influenza A virus (strain swl A/California/04/2009 H1N1)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsHan J / Ward A
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)75N93019C00051 United States
CitationJournal: Sci Transl Med / Year: 2021
Title: First exposure to the pandemic H1N1 virus induced broadly neutralizing antibodies targeting hemagglutinin head epitopes.
Authors: Jenna J Guthmiller / Julianna Han / Lei Li / Alec W Freyn / Sean T H Liu / Olivia Stovicek / Christopher T Stamper / Haley L Dugan / Micah E Tepora / Henry A Utset / Dalia J Bitar / Natalie ...Authors: Jenna J Guthmiller / Julianna Han / Lei Li / Alec W Freyn / Sean T H Liu / Olivia Stovicek / Christopher T Stamper / Haley L Dugan / Micah E Tepora / Henry A Utset / Dalia J Bitar / Natalie J Hamel / Siriruk Changrob / Nai-Ying Zheng / Min Huang / Florian Krammer / Raffael Nachbagauer / Peter Palese / Andrew B Ward / Patrick C Wilson /
Abstract: Broadly neutralizing antibodies are critical for protection against both drifted and shifted influenza viruses. Here, we reveal that first exposure to the 2009 pandemic H1N1 influenza virus recalls ...Broadly neutralizing antibodies are critical for protection against both drifted and shifted influenza viruses. Here, we reveal that first exposure to the 2009 pandemic H1N1 influenza virus recalls memory B cells that are specific to the conserved receptor-binding site (RBS) or lateral patch epitopes of the hemagglutinin (HA) head domain. Monoclonal antibodies (mAbs) generated against these epitopes are broadly neutralizing against H1N1 viruses spanning 40 years of viral evolution and provide potent protection in vivo. Lateral patch-targeting antibodies demonstrated near universal binding to H1 viruses, and RBS-binding antibodies commonly cross-reacted with H3N2 viruses and influenza B viruses. Lateral patch-targeting mAbs were restricted to expressing the variable heavy-chain gene VH3-23 with or without the variable kappa-chain gene VK1-33 and often had a Y-x-R motif within the heavy-chain complementarity determining region 3 to make key contacts with HA. Moreover, lateral patch antibodies that used both VH3-23 and VK1-33 maintained neutralizing capability with recent pH1N1 strains that acquired mutations near the lateral patch. RBS-binding mAbs used a diverse repertoire but targeted the RBS epitope similarly and made extensive contacts with the major antigenic site Sb. Together, our data indicate that RBS- and lateral patch-targeting clones are abundant within the human memory B cell pool, and universal vaccine strategies should aim to drive antibodies against both conserved head and stalk epitopes.
History
DepositionApr 6, 2021-
Header (metadata) releaseJul 28, 2021-
Map releaseJul 28, 2021-
UpdateJul 28, 2021-
Current statusJul 28, 2021Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.389
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by cylindrical radius
  • Surface level: 0.389
  • Imaged by UCSF Chimera
  • Download
  • Surface view with fitted model
  • Atomic models: PDB-7mem
  • Surface level: 0.389
  • Imaged by UCSF Chimera
  • Download
  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-7mem
  • Imaged by Jmol
  • Download
Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_23792.png

Downloads & links

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Map

FileDownload / File: emd_23792.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryoEM map of monoclonal Fab 045-09 2B05 binding the lateral patch of H1 HA
Voxel sizeX=Y=Z: 1.03 Å
Density
Contour LevelBy AUTHOR: 0.389 / Movie #1: 0.389
Minimum - Maximum-1.3803498 - 2.1330953
Average (Standard dev.)-0.00029952542 (±0.055529073)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 329.59998 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.031.031.03
M x/y/z320320320
origin x/y/z0.0000.0000.000
length x/y/z329.600329.600329.600
α/β/γ90.00090.00090.000
start NX/NY/NZ1331310
NX/NY/NZ223226424
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS320320320
D min/max/mean-1.3802.133-0.000

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Supplemental data

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Mask #1

Fileemd_23792_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: CryoEM half map of monoclonal Fab 045-09 2B05...

Fileemd_23792_half_map_1.map
AnnotationCryoEM half map of monoclonal Fab 045-09 2B05 binding the lateral patch of H1 HA
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: CryoEM half map of monoclonal Fab 045-09 2B05...

Fileemd_23792_half_map_2.map
AnnotationCryoEM half map of monoclonal Fab 045-09 2B05 binding the lateral patch of H1 HA
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : CryoEM structure of monoclonal Fab 045-09 2B05 binding the latera...

EntireName: CryoEM structure of monoclonal Fab 045-09 2B05 binding the lateral patch of H1 HA
Components
  • Complex: CryoEM structure of monoclonal Fab 045-09 2B05 binding the lateral patch of H1 HA
    • Complex: monoclonal Fab 045-09 2B05
      • Protein or peptide: Light chain of monoclonal antibody 045-09 2B05
      • Protein or peptide: Heavy chain of monoclonal antibody 045-09 2B05
    • Complex: Hemagglutinin
      • Protein or peptide: Hemagglutinin HA1 chain
      • Protein or peptide: Hemagglutinin HA2 chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: CryoEM structure of monoclonal Fab 045-09 2B05 binding the latera...

SupramoleculeName: CryoEM structure of monoclonal Fab 045-09 2B05 binding the lateral patch of H1 HA
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4

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Supramolecule #2: monoclonal Fab 045-09 2B05

SupramoleculeName: monoclonal Fab 045-09 2B05 / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #2-#3
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: Hemagglutinin

SupramoleculeName: Hemagglutinin / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #1, #4
Source (natural)Organism: Influenza A virus (strain swl A/California/04/2009 H1N1)

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Macromolecule #1: Hemagglutinin HA1 chain

MacromoleculeName: Hemagglutinin HA1 chain / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Influenza A virus (strain swl A/California/04/2009 H1N1)
Strain: swl A/California/04/2009 H1N1
Molecular weightTheoretical: 36.729402 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: ADPGDTLCIG YHANNSTDTV DTVLEKNVTV THSVNLLEDK HNGKLCKLRG VAPLHLGKCN IAGWILGNPE CESLSTASSW SYIVETPSS DNGTCYPGDF IDYEELREQL SSVSSFERFE IFPKTSSWPN HDSNKGVTAA CPHAGAKSFY KNLIWLVKKG N SYPKLSKS ...String:
ADPGDTLCIG YHANNSTDTV DTVLEKNVTV THSVNLLEDK HNGKLCKLRG VAPLHLGKCN IAGWILGNPE CESLSTASSW SYIVETPSS DNGTCYPGDF IDYEELREQL SSVSSFERFE IFPKTSSWPN HDSNKGVTAA CPHAGAKSFY KNLIWLVKKG N SYPKLSKS YINDKGKEVL VLWGIHHPST SADQQSLYQN ADTYVFVGSS RYSKKFKPEI AIRPKVRDQE GRMNYYWTLV EP GDKITFE ATGNLVVPRY AFAMERNAGS GIIISDTPVH DCNTTCQTPK GAINTSLPFQ NIHPITIGKC PKYVKSTKLR LAT GLRNIP SIQSR

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Macromolecule #2: Light chain of monoclonal antibody 045-09 2B05

MacromoleculeName: Light chain of monoclonal antibody 045-09 2B05 / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human) / Cell: B cell
Molecular weightTheoretical: 11.76912 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
DIQMTQSPSS LSAFVGDRVT IACQASQDIR IHLNWYQQKP GKAPKLLIYD ASNLEAGVPS RFSGSGSGTD FTFTISSLQP EDIATYYCQ HYHNLPRTFG GGTKVEIK

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Macromolecule #3: Heavy chain of monoclonal antibody 045-09 2B05

MacromoleculeName: Heavy chain of monoclonal antibody 045-09 2B05 / type: protein_or_peptide / ID: 3 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human) / Cell: B cell
Molecular weightTheoretical: 12.805238 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
VQLLESGGGL VQPGGSLSLS CAASGFTFSS FAMSWVRQAP VKGLEWVSMI SAGGGNTYYA DSVKGRFTIS RDNSKSTLYL QMSSLTAED TAVYYCAKSD SSGFQYGRRE FWGQGTLVTV S

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Macromolecule #4: Hemagglutinin HA2 chain

MacromoleculeName: Hemagglutinin HA2 chain / type: protein_or_peptide / ID: 4 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Influenza A virus (strain swl A/California/04/2009 H1N1)
Strain: swl A/California/04/2009 H1N1
Molecular weightTheoretical: 19.904998 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
GLFGAIAGFI EGGWTGMVDG WYGYHHQNEQ GSGYAADLKS TQNAIDGITN KVNSVIEKMN TQFTAVGKEF NHLEKRIENL NKKVDDGFL DIWTYNAELL VLLENERTLD YHDSNVKNLY EKVRSQLKNN AKEIGNGCFE FYHKCDNTCM ESVKNGTYDY P KYSEEAKL NREEID

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Macromolecule #7: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 7 / Number of copies: 6 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.75 mg/mL
BufferpH: 7.4 / Details: TBS + LMNG
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 400 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK III

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal magnification: 29000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average electron dose: 49.27 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

4m4y

Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 2) / Number images used: 27888
FSC plot (resolution estimation)

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