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- EMDB-76455: Cryo-EM structure of B/Phuket/3037/2013 hemagglutinin trimer in c... -

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Entry
Database: EMDB / ID: EMD-76455
TitleCryo-EM structure of B/Phuket/3037/2013 hemagglutinin trimer in complex with two KL-BHA-3D7 Fab fragments
Map dataCryo-EM structure of B/Phuket/3073/2013 trimer in complex with two KL-BHA-3D7 Fab fragments
Sample
  • Complex: Cryo-EM structure of B/Phuket/3073/2013 hemagglutinin trimer in complex with two KL-BHA-3D7 Fab fragments
    • Protein or peptide: Hemagglutinin
    • Protein or peptide: KL-BHA-3D7 heavy chain
    • Protein or peptide: KL-BHA-3D7 light chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Keywordshemagglutinin / Fab / viral glycoprotein / Viral protein-Immune System complex
Function / homology
Function and homology information


viral budding from plasma membrane / host cell surface receptor binding / endocytosis involved in viral entry into host cell / 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 / membrane
Similarity search - Function
Haemagglutinin, influenzavirus B / Haemagglutinin, HA1 chain, alpha/beta domain superfamily / Haemagglutinin / Haemagglutinin, influenzavirus A/B / Viral capsid/haemagglutinin protein
Similarity search - Domain/homology
Biological speciesMus musculus (house mouse) / Influenza B virus (B/Beijing/13-21/2013)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.98 Å
AuthorsCivljak A / Bonnettaz B / Bajic G
Funding support United States, 5 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI117287 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI109946 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI097092 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)HHSN272201400008C United States
Other private United States
CitationJournal: J Virol / Year: 2026
Title: Broadly reactive antibodies against influenza B virus hemagglutinin neutralize and protect through distinct structural mechanisms.
Authors: Disha Bhavsar / Alesandro Civljak / Bruno Bonnettaz / Guha Asthagiri Arunkumar / Florian Krammer / Goran Bajic /
Abstract: Influenza B viruses contribute substantially to seasonal disease burden; however, the structural basis by which antibodies recognize the major glycoprotein hemagglutinin (HA) and mediate antiviral ...Influenza B viruses contribute substantially to seasonal disease burden; however, the structural basis by which antibodies recognize the major glycoprotein hemagglutinin (HA) and mediate antiviral activity remains incompletely defined. Influenza B virus used to circulate as two antigenically distinct lineages, B/Victoria/2/1987-like and B/Yamagata/16/1988-like, although the latter has not been detected in global surveillance in recent years. Antigenic drift in HA contributes to reduced vaccine effectiveness; however, the structural and functional basis by which antibodies recognize influenza B virus HA and mediate antiviral activity remains incompletely defined and thus thwarts our efforts in guiding next-generation vaccine design for broad protection. We characterize four murine monoclonal antibodies (mAb) that broadly bind and neutralize influenza B viruses spanning isolates across four decades of antigenic drift. Using cryo-electron microscopy coupled with and functional assays, we show that these antibodies target distinct regions of HA and confer antiviral activity through multiple mechanisms. One antibody engages the receptor-binding site and potently inhibits hemagglutination, whereas others interfere with viral egress and inhibit neuraminidase (NA) activity, suggesting steric occlusion of NA. A medial-junction antibody additionally induces antibody-dependent cellular cytotoxicity . Despite these mechanistic differences, all antibodies confer complete protection in mice when administered prophylactically or therapeutically. Together, these findings define distinct modes of antibody recognition of influenza B virus HA and link epitope specificity to antiviral function, providing a mechanistic understanding of correlates of immune protection and informing efforts to elicit broadly protective antibody responses against influenza B viruses.IMPORTANCEInfluenza B viruses cause substantial seasonal illness, particularly in children; however, antibody responses against influenza B virus remain less well understood than those against influenza A virus. Here, we identified four antibodies that broadly recognize influenza B virus hemagglutinin and protect through distinct mechanisms. We determined cryo-electron microscopy structures of three antibody-hemagglutinin complexes to define their epitopes and explain their molecular mechanisms of action. One antibody blocks viral attachment by engaging the receptor-binding site, whereas antibodies targeting the medial junction act through post-entry antiviral activity, neuraminidase inhibition, or immune effector functions. Although the antibodies differed in neutralizing potency, all protected mice when administered before infection, and several remained effective after infection. These findings show that broad protection against influenza B virus can arise through multiple antibody targets and mechanisms, informing the evaluation and design of future vaccines and antibody-based therapies.
History
DepositionApr 7, 2026-
Header (metadata) releaseAug 26, 2026-
Map releaseAug 26, 2026-
UpdateSep 16, 2026-
Current statusSep 16, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_76455.png

Downloads & links

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Map

FileDownload / File: emd_76455.map.gz / Format: CCP4 / Size: 421.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM structure of B/Phuket/3073/2013 trimer in complex with two KL-BHA-3D7 Fab fragments
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 480 pix.
= 406.08 Å		0.85 Å/pix.
x 480 pix.
= 406.08 Å		0.85 Å/pix.
x 480 pix.
= 406.08 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.846 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.12
Minimum - Maximum-0.0018246733 - 1.9221586
Average (Standard dev.)0.00061936985 (±0.018684708)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions480480480
Spacing480480480
CellA=B=C: 406.08002 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half Map A

Fileemd_76455_half_map_1.map
AnnotationHalf Map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half Map B

Fileemd_76455_half_map_2.map
AnnotationHalf Map B
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Cryo-EM structure of B/Phuket/3073/2013 hemagglutinin trimer in c...

EntireName: Cryo-EM structure of B/Phuket/3073/2013 hemagglutinin trimer in complex with two KL-BHA-3D7 Fab fragments
Components
  • Complex: Cryo-EM structure of B/Phuket/3073/2013 hemagglutinin trimer in complex with two KL-BHA-3D7 Fab fragments
    • Protein or peptide: Hemagglutinin
    • Protein or peptide: KL-BHA-3D7 heavy chain
    • Protein or peptide: KL-BHA-3D7 light chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Cryo-EM structure of B/Phuket/3073/2013 hemagglutinin trimer in c...

SupramoleculeName: Cryo-EM structure of B/Phuket/3073/2013 hemagglutinin trimer in complex with two KL-BHA-3D7 Fab fragments
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Details: B/Phuket/3073/2013 hemagglutinin expressed using Sf9 insect cells
Source (natural)Organism: Mus musculus (house mouse)

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Macromolecule #1: Hemagglutinin

MacromoleculeName: Hemagglutinin / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Influenza B virus (B/Beijing/13-21/2013) / Strain: B/Beijing/13-21/2013
Molecular weightTheoretical: 56.616316 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: DRICTGITSS NSPHVVKTAT QGEVNVTGVI PLTTTPTKSY FANLKGTRTR GKLCPDCLNC TDLDVALGRP MCVGTTPSAK ASILHEVRP VTSGCFPIMH DRTKIRQLPN LLRGYEKIRL STQNVIDAEK APGGPYRLGT SGSCPNATSK IGFFATMAWA V PKDNYKNA ...String:
DRICTGITSS NSPHVVKTAT QGEVNVTGVI PLTTTPTKSY FANLKGTRTR GKLCPDCLNC TDLDVALGRP MCVGTTPSAK ASILHEVRP VTSGCFPIMH DRTKIRQLPN LLRGYEKIRL STQNVIDAEK APGGPYRLGT SGSCPNATSK IGFFATMAWA V PKDNYKNA TNPLTVEVPY ICTEGEDQIT VWGFHSDNKI QMKSLYGDSN PQKFTSSANG VTTHYVSQIG DFPDQTEDGG LP QSGRIVV DYMMQKPGKT GTIVYQRGVL LPQKVWCASG RSKVIKGSLP LIGEADCLHE EYGGLNKSKP YYTGKHAKAI GNC PIWVKT PLKLANGTKY RPPAKLLKER GFFGAIAGFL EGGWEGMIAG WHGYTSHGAH GVAVAADLKS TQEAINKITK NLNS LSELE VKNLQRLSGA MDELHNEILE LDEKVDDLRA DTISSQIELA VLLSNEGIIN SEDEHLLALE RKLKKMLGPS AVDIG NGCF ETKHKCNQTC LDRIAAGTFN AGEFSLPTFD SLNITAAS

UniProtKB: Hemagglutinin

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Macromolecule #2: KL-BHA-3D7 heavy chain

MacromoleculeName: KL-BHA-3D7 heavy chain / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 13.419956 KDa
Recombinant expressionOrganism: Mus musculus (house mouse)
SequenceString:
DVQLVESGGG LVQPGGSRKL SCAASGFTFS SFGMHWVRQA PEKGLEWVAY ISSGSTIIYY ADTVKGRFTI SRDNPKNTLF LQMTSLRSE DTAMYYCARS GSSYVRDWYF DVWGAGTTVT VSS

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Macromolecule #3: KL-BHA-3D7 light chain

MacromoleculeName: KL-BHA-3D7 light chain / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 12.192493 KDa
Recombinant expressionOrganism: Mus musculus (house mouse)
SequenceString:
DIVLTQSPAS LAVSLGQRAT ISCRASESVD YYGDSFMHWY QQKPGQPPKL LIYRASNLES GIPARFSGSG SRTDFTLTIN PVEADDVAT YFCQQSNQDP WTFGGGTKLE IK

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Macromolecule #6: 2-acetamido-2-deoxy-beta-D-glucopyranose

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

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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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

BufferpH: 7.5
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 58.69 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.98 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 118085
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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