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- PDB-7u8l: Crystal structure of chimeric hemagglutinin cH15/3 in complex wit... -

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Basic information

Entry
Database: PDB / ID: 7u8l
TitleCrystal structure of chimeric hemagglutinin cH15/3 in complex with broad protective antibody 31.a.83
Components
  • Antibody Fab light chain
  • Hemagglutinin HA1 subunit
  • Hemagglutinin HA2 subunit
  • antibody Fab heavy chain
KeywordsVIRAL PROTEIN/Immune System / Universal vaccine design / chimeric influenza hemagglutinin / HA trimer interface and stem / VIRAL PROTEIN-Immune System complex
Function / homology
Function and homology information


viral budding from plasma membrane / clathrin-dependent endocytosis of virus by host cell / host cell surface receptor binding / 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 A / Haemagglutinin, HA1 chain, alpha/beta domain superfamily / Haemagglutinin / Haemagglutinin, influenzavirus A/B / Viral capsid/haemagglutinin protein
Similarity search - Domain/homology
Biological speciesInfluenza A virus
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 4.56 Å
AuthorsZhu, X. / Wilson, I.A.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)75N93109C00051 United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2022
Title: Influenza chimeric hemagglutinin structures in complex with broadly protective antibodies to the stem and trimer interface.
Authors: Xueyong Zhu / Julianna Han / Weina Sun / Eduard Puente-Massaguer / Wenli Yu / Peter Palese / Florian Krammer / Andrew B Ward / Ian A Wilson /
Abstract: Influenza virus hemagglutinin (HA) has been the primary target for influenza vaccine development. Broadly protective antibodies targeting conserved regions of the HA unlock the possibility of ...Influenza virus hemagglutinin (HA) has been the primary target for influenza vaccine development. Broadly protective antibodies targeting conserved regions of the HA unlock the possibility of generating universal influenza immunity. Two group 2 influenza A chimeric HAs, cH4/3 and cH15/3, were previously designed to elicit antibodies to the conserved HA stem. Here, we show by X-ray crystallography and negative-stain electron microscopy that a broadly protective antistem antibody can stably bind to cH4/3 and cH15/3 HAs, thereby validating their potential as universal vaccine immunogens. Furthermore, flexibility was observed in the head domain of the chimeric HA structures, suggesting that antibodies could also potentially interact with the head interface epitope. Our structural and binding studies demonstrated that a broadly protective antihead trimeric interface antibody could indeed target the more open head domain of the cH15/3 HA trimer. Thus, in addition to inducing broadly protective antibodies against the conserved HA stem, chimeric HAs may also be able to elicit antibodies against the conserved trimer interface in the HA head domain, thereby increasing the vaccine efficacy.
History
DepositionMar 8, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 8, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.2Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Hemagglutinin HA1 subunit
B: Hemagglutinin HA2 subunit
L: Antibody Fab light chain
H: antibody Fab heavy chain


Theoretical massNumber of molelcules
Total (without water)105,1524
Polymers105,1524
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)156.168, 156.168, 114.019
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number150
Space group name H-MP321

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Components

#1: Protein Hemagglutinin HA1 subunit


Mass: 36593.133 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Influenza A virus / Production host: Trichoplusia ni (cabbage looper)
#2: Protein Hemagglutinin HA2 subunit


Mass: 20152.406 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Influenza A virus / Gene: HA / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: A0A2Z4LK48
#3: Antibody Antibody Fab light chain


Mass: 23512.111 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)
#4: Antibody antibody Fab heavy chain


Mass: 24894.752 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 3.79 Å3/Da / Density % sol: 67.54 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 0.1 M Tris, pH 7.0, 40% (w/v) polyethylene glycol 300 and 5% (w/v) polyethylene glycol 1000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-B / Wavelength: 1.0332 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jun 25, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 4.56→46.64 Å / Num. obs: 9360 / % possible obs: 99.5 % / Redundancy: 12.3 % / CC1/2: 0.994 / Rpim(I) all: 0.06 / Rsym value: 0.2 / Net I/σ(I): 7.5
Reflection shellResolution: 4.56→4.68 Å / Redundancy: 4.2 % / Mean I/σ(I) obs: 0.9 / Num. unique obs: 431 / CC1/2: 0.555 / Rpim(I) all: 0.37 / Rsym value: 0.78 / % possible all: 95.4

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
PDB_EXTRACT3.27data extraction
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5TG8,4WE8,5KAQ

5tg8

4we8

5kaq


Resolution: 4.56→46.64 Å / SU ML: 0.69 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 31.39 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.3052 468 5 %
Rwork0.3003 8883 -
obs0.3005 9351 98.89 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 255.61 Å2 / Biso mean: 170.1286 Å2 / Biso min: 98.35 Å2
Refinement stepCycle: final / Resolution: 4.56→46.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7212 0 0 0 7212
Num. residues----933
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 3

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
4.56-4.680.34151520.34112866301897
5.22-6.570.34521620.326529263088100
6.57-46.640.26681540.274130913245100

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