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- PDB-12ie: Cryo-EM structure of B/Lee/1940 hemagglutinin trimer in complex w... -

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Basic information

Entry
Database: PDB / ID: 12ie
TitleCryo-EM structure of B/Lee/1940 hemagglutinin trimer in complex with three KL-BHA-4C2 Fab fragments
Components
  • Hemagglutinin
  • KL-BHA-4C2 heavy chain
  • KL-BHA-4C2 light chain
KeywordsImmune System/Viral Protein / hemagglutinin / Fab / viral glycoprotein / Immune System-Viral Protein complex
Function / homology:
Function and homology information
Biological speciesMus musculus (house mouse)
Influenza B virus
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.61 Å
AuthorsCivljak, A. / Bonnettaz, B. / Bajic, G.
Funding support United States, 5items
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, 2026Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 26, 2026Provider: repository / Type: Initial release
Revision 1.0Aug 26, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.1Sep 16, 2026Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update
Revision 1.1Sep 16, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin
Data content type: EM metadata / EM metadata ...EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
H: KL-BHA-4C2 heavy chain
A: Hemagglutinin
L: KL-BHA-4C2 light chain
N: KL-BHA-4C2 light chain
E: KL-BHA-4C2 light chain
C: Hemagglutinin
B: Hemagglutinin
D: KL-BHA-4C2 heavy chain
M: KL-BHA-4C2 heavy chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)249,59015
Polymers246,5579
Non-polymers3,0336
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails (eV)
d_1ens_1chain "C"
d_2ens_1chain "B"
d_3ens_1chain "A"
d_1ens_2chain "D"
d_2ens_2chain "H"
d_3ens_2chain "M"
d_1ens_3chain "N"
d_2ens_3chain "L"
d_3ens_3chain "E"

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
d_11ens_1SERSERASPASPCF12 - 45812 - 458
d_12ens_1NAGNAGNAGNAGIL1
d_13ens_1NAGNAGNAGNAGIL2
d_14ens_1BMABMABMABMAIL3
d_15ens_1NAGNAGNAGNAGJM1
d_16ens_1NAGNAGNAGNAGJM2
d_21ens_1SERSERASPASPBG12 - 45812 - 458
d_22ens_1NAGNAGNAGNAGKN1
d_23ens_1NAGNAGNAGNAGKN2
d_24ens_1BMABMABMABMAKN3
d_25ens_1NAGNAGNAGNAGOO1
d_26ens_1NAGNAGNAGNAGOO2
d_31ens_1SERSERASPASPAB12 - 45812 - 458
d_32ens_1NAGNAGNAGNAGFJ1
d_33ens_1NAGNAGNAGNAGFJ2
d_34ens_1BMABMABMABMAFJ3
d_35ens_1NAGNAGNAGNAGGK1
d_36ens_1NAGNAGNAGNAGGK2
d_11ens_2GLNGLNSERSERDH1 - 1201 - 120
d_21ens_2GLNGLNSERSERHA1 - 1201 - 120
d_31ens_2GLNGLNSERSERMI1 - 1201 - 120
d_11ens_3ASPASPLYSLYSND1 - 1111 - 111
d_21ens_3ASPASPLYSLYSLC1 - 1111 - 111
d_31ens_3ASPASPLYSLYSEE1 - 1111 - 111

NCS ensembles :
ID
ens_1
ens_2
ens_3

NCS oper:
IDCodeMatrixVector
1given(-0.500825358703, 0.865548349783, -0.00011944962442), (-0.865548316959, -0.500825287661, 0.000377159026014), (0.000266625980061, 0.00029228022587, 0.999999921741)137.309519328, 511.238535171, -0.124900601236
2given(-0.500644853512, -0.865652772681, 8.83251139208E-5), (0.865652772772, -0.500644838047, 0.000152084613216), (-8.74329547581E-5, 0.000152599258676, 0.999999984534)511.292927052, 137.184210064, -0.00664451732632
3given(-0.499859583129, 0.866106208986, -0.000657197890797), (-0.866103352294, -0.499859678785, -0.00229884080394), (-0.00231954702036, -0.000579896309599, 0.999997141707)137.091932208, 511.740914775, 0.644030965671
4given(-0.500734993027, -0.865600630352, -0.000124469756006), (0.865599928104, -0.500734760766, 0.00120988690623), (-0.00110960520218, 0.000498091699703, 0.99999926034)511.37246438, 136.974654256, 0.178601964757
5given(-0.497804263467, -0.867289206901, -0.00058895422578), (0.867282326303, -0.497802828601, 0.00370274496314), (-0.00350453382195, 0.00133245263816, 0.999992971382)511.172093771, 135.285465746, 0.521598905963
6given(-0.501908006774, 0.864916744625, -0.00271617446543), (-0.864918695901, -0.501911452947, -0.000736805316797), (-0.00200055432843, 0.00197946158854, 0.999996039749)138.364380973, 511.61472852, -0.0195605663644

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Components

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


Mass: 13255.941 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Mus musculus (house mouse)
#2: Protein Hemagglutinin


Mass: 56640.168 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Influenza B virus (B/Lee/1940) / Strain: B/Lee/1940 / Gene: HA / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q0PLR5
#3: Antibody KL-BHA-4C2 light chain


Mass: 12289.717 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Mus musculus (house mouse)
#4: Polysaccharide beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}LINUCSPDB-CARE
#5: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
Has ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Cryo-EM structure of B/Lee/1940 hemagglutinin trimer in complex with three KL-BHA-4C2 Fab fragments
Type: COMPLEX
Details: B/Lee/1940 hemagglutinin expressed using Sf9 insect cells
Entity ID: #1-#3 / Source: RECOMBINANT
Source (natural)Organism: Mus musculus (house mouse)
Source (recombinant)Organism: Mus musculus (house mouse)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: SPOT SCAN
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 1500 nm
Image recordingElectron dose: 58.92 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1Topazparticle selection
2PHENIX1.21.2_5419model refinement
5cryoSPARCCTF correction
10cryoSPARCinitial Euler assignment
11cryoSPARCfinal Euler assignment
12cryoSPARCclassification
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C3 (3 fold cyclic)
3D reconstructionResolution: 2.61 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 80242 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 46.44 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.003514937
ELECTRON MICROSCOPYf_angle_d0.704320277
ELECTRON MICROSCOPYf_chiral_restr0.04972340
ELECTRON MICROSCOPYf_plane_restr0.00672592
ELECTRON MICROSCOPYf_dihedral_angle_d5.87962316
Refine LS restraints NCS
Ens-IDDom-IDAsym-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2FCELECTRON MICROSCOPYNCS constraints8.58244040306E-13
ens_1d_3FCELECTRON MICROSCOPYNCS constraints1.98120688767E-10
ens_2d_2HDELECTRON MICROSCOPYNCS constraints9.02721152232E-11
ens_2d_3HDELECTRON MICROSCOPYNCS constraints4.07772971273E-13
ens_3d_2DNELECTRON MICROSCOPYNCS constraints1.40650218384E-10
ens_3d_3DNELECTRON MICROSCOPYNCS constraints2.59451123384E-13

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