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- EMDB-76454: Cryo-EM structure of B/Lee/1940 hemagglutinin trimer in complex w... -

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Entry
Database: EMDB / ID: EMD-76454
TitleCryo-EM structure of B/Lee/1940 hemagglutinin trimer in complex with three KL-BHA-4C2 Fab fragments
Map datastructure of B/Lee/1940 hemagglutinin trimer in complex with three KL-BHA-4C2 Fab fragments
Sample
  • Complex: Cryo-EM structure of B/Lee/1940 hemagglutinin trimer in complex with three KL-BHA-4C2 Fab fragments
    • Protein or peptide: KL-BHA-4C2 heavy chain
    • Protein or peptide: Hemagglutinin
    • Protein or peptide: KL-BHA-4C2 light chain
Keywordshemagglutinin / Fab / viral glycoprotein / Immune System-Viral Protein complex
Function / homology:
Function and homology information
Biological speciesMus musculus (house mouse) / Influenza B virus (B/Lee/1940)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.61 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_76454.png

Downloads & links

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Map

FileDownload / File: emd_76454.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationstructure of B/Lee/1940 hemagglutinin trimer in complex with three KL-BHA-4C2 Fab fragments
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.84 Å/pix.
x 512 pix.
= 432.128 Å		0.84 Å/pix.
x 512 pix.
= 432.128 Å		0.84 Å/pix.
x 512 pix.
= 432.128 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.844 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.12
Minimum - Maximum-0.001797935 - 2.133005
Average (Standard dev.)0.00047048042 (±0.016254606)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 432.128 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half map A

Fileemd_76454_half_map_1.map
AnnotationHalf map A
Projections & Slices
AxesZYX

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Histogram

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Half map: Half map B

Fileemd_76454_half_map_2.map
AnnotationHalf map B
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Sample components

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Entire : Cryo-EM structure of B/Lee/1940 hemagglutinin trimer in complex w...

EntireName: Cryo-EM structure of B/Lee/1940 hemagglutinin trimer in complex with three KL-BHA-4C2 Fab fragments
Components
  • Complex: Cryo-EM structure of B/Lee/1940 hemagglutinin trimer in complex with three KL-BHA-4C2 Fab fragments
    • Protein or peptide: KL-BHA-4C2 heavy chain
    • Protein or peptide: Hemagglutinin
    • Protein or peptide: KL-BHA-4C2 light chain

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Supramolecule #1: Cryo-EM structure of B/Lee/1940 hemagglutinin trimer in complex w...

SupramoleculeName: Cryo-EM structure of B/Lee/1940 hemagglutinin trimer in complex with three KL-BHA-4C2 Fab fragments
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Details: B/Lee/1940 hemagglutinin expressed using Sf9 insect cells
Source (natural)Organism: Mus musculus (house mouse)

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Macromolecule #1: KL-BHA-4C2 heavy chain

MacromoleculeName: KL-BHA-4C2 heavy chain / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 13.255941 KDa
Recombinant expressionOrganism: Mus musculus (house mouse)
SequenceString:
QVTLKESGPG ILRPSQTLSL TCSFSGFSLS TSGMGVGWIR QPSGKGLEWL AHVWWDDDKY YNPSLKSGLT ISKDTSRNQV FLKITSVDT ADSATYYCAR KVLFMRAMDY WGQGTSVTVS S

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Macromolecule #2: Hemagglutinin

MacromoleculeName: Hemagglutinin / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Influenza B virus (B/Lee/1940) / Strain: B/Lee/1940
Molecular weightTheoretical: 56.640168 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: DRICTGITSS NSPHVIKTAT QGEVNVTGVI PLTTTPTRSH FANLKGTQTR GKLCPNCFDC TDLDVALGRP KCMGNIPSAK VSILHEVKP VTSGCFPIMH DRTKIRQLPN LLRGYENIRL STSNVINAET APGGPYKVGT SGSCPNVANR NGFFNTMAWV I PQDNNKTA ...String:
DRICTGITSS NSPHVIKTAT QGEVNVTGVI PLTTTPTRSH FANLKGTQTR GKLCPNCFDC TDLDVALGRP KCMGNIPSAK VSILHEVKP VTSGCFPIMH DRTKIRQLPN LLRGYENIRL STSNVINAET APGGPYKVGT SGSCPNVANR NGFFNTMAWV I PQDNNKTA INPVTVEVPY ICSEGEDQIT VWGFHSDDKT QMERLYGDSN PQKFTSSANG VTTHYVSQIG GFPNQTEDEG LK QSGRIVV DYMVQKPGKT GTIVYQRGIL LPQKVWCASG RSKVIKGSLP LIGEADCLHE KYGGLNKSKP YYTGEHAKAI GNC PIWVKT PLKLANGTKY RPPAKLLKER GFFGAIAGFL EGGWEGMIAG WHGYTSHGAH GVAVAADLKS TQEAINKITK NLNS LSELE VKNLQRLSGA MNGLHDEILE LDEKVDDLRA DTISSQIELA VLLSNEGIIN SEDEHLLALE RKLKKMLGPS AVEIG NGCF ETKHKCNQTC LDRIAAGTFN AGDFSLPTFD SLNITAAS

UniProtKB: UNIPROTKB: Q0PLR5

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Macromolecule #3: KL-BHA-4C2 light chain

MacromoleculeName: KL-BHA-4C2 light chain / type: protein_or_peptide / ID: 3 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 12.289717 KDa
Recombinant expressionOrganism: Mus musculus (house mouse)
SequenceString:
DIVLIRLTIG QAVVSTQRAT ISCRASESVD SYGNIYMHWY QQKPGQPPKL LIYRASNLES GIPARFSGSG SRTDFTLTIN PVEADDVAT YYCQQSTEDP WTFGGGTKLE IK

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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: 58.92 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 correctionSoftware - Name: cryoSPARC / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionApplied symmetry - Point group: C3 (3 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.61 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 80242
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final 3D classificationSoftware - Name: cryoSPARC
FSC plot (resolution estimation)

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