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- PDB-7u8m: Crystal structure of chimeric hemagglutinin cH15/3 in complex wit... -

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Basic information

Entry
Database: PDB / ID: 7u8m
TitleCrystal structure of chimeric hemagglutinin cH15/3 in complex with broad protective antibodies 31.a.83 and FluA-20
Components
  • (antibody FluA-20 Fab ...) x 2
  • (hemagglutinin ...) x 2
  • Antibody 31.a.83 Fab light chain
  • antibody 31.a.83 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 / membrane => GO:0016020 / 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 speciesInfluenza A virus
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 5.39 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 ...chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id ..._struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: hemagglutinin HA1 subunit
B: hemagglutinin HA2 subunit
L: Antibody 31.a.83 Fab light chain
H: antibody 31.a.83 Fab heavy chain
C: hemagglutinin HA1 subunit
D: hemagglutinin HA2 subunit
E: Antibody 31.a.83 Fab light chain
F: antibody 31.a.83 Fab heavy chain
G: hemagglutinin HA1 subunit
I: hemagglutinin HA2 subunit
J: Antibody 31.a.83 Fab light chain
K: antibody 31.a.83 Fab heavy chain
N: antibody FluA-20 Fab heavy chain
O: antibody FluA-20 Fab light chain
Q: antibody FluA-20 Fab heavy chain
R: antibody FluA-20 Fab light chain
T: antibody FluA-20 Fab heavy chain
U: antibody FluA-20 Fab light chain


Theoretical massNumber of molelcules
Total (without water)458,95718
Polymers458,95718
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)272.922, 155.729, 156.893
Angle α, β, γ (deg.)90.000, 94.630, 90.000
Int Tables number5
Space group name H-MC121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11chain A
21chain C
31chain G
12chain B
22chain D
32chain I
13chain E
23chain J
33chain L
14chain F
24chain H
34chain K
15chain N
25chain Q
35chain T
16chain O
26chain R
36chain U

NCS domain segments:

Component-ID: 1

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11ALAALAGLUGLUchain AAA11 - 3254 - 329
21ALAALAGLUGLUchain CCE11 - 3254 - 329
31ALAALAGLUGLUchain GGI11 - 3254 - 329
12GLYGLYILEILEchain BBB1 - 1731 - 173
22GLYGLYILEILEchain DDF1 - 1731 - 173
32GLYGLYILEILEchain IIJ1 - 1731 - 173
13GLUGLUCYSCYSchain EEG1 - 2141 - 214
23GLUGLUCYSCYSchain JJK1 - 2141 - 214
33GLUGLUCYSCYSchain LLC1 - 2141 - 214
14GLUGLULYSLYSchain FFH1 - 2281 - 232
24GLUGLULYSLYSchain HHD1 - 2281 - 232
34GLUGLULYSLYSchain KKL1 - 2281 - 232
15GLNGLNLYSLYSchain NNM1 - 2141 - 227
25GLNGLNLYSLYSchain QQO1 - 2141 - 227
35GLNGLNLYSLYSchain TTQ1 - 2141 - 227
16ASPASPGLUGLUchain OON1 - 2131 - 213
26ASPASPGLUGLUchain RRP1 - 2131 - 213
36ASPASPGLUGLUchain UUR1 - 2131 - 213

NCS ensembles :
ID
1
2
3
4
5
6

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Components

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Hemagglutinin ... , 2 types, 6 molecules ACGBDI

#1: Protein hemagglutinin HA1 subunit


Mass: 36593.133 Da / Num. of mol.: 3
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.: 3
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

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Antibody , 4 types, 12 molecules LEJHFKNQTORU

#3: Antibody Antibody 31.a.83 Fab light chain


Mass: 23512.111 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)
#4: Antibody antibody 31.a.83 Fab heavy chain


Mass: 24894.752 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)
#5: Antibody antibody FluA-20 Fab heavy chain


Mass: 24325.158 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)
#6: Antibody antibody FluA-20 Fab light chain


Mass: 23508.186 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)

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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: 3.6 Å3/Da / Density % sol: 65.86 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 0.1 M sodium cacodylate, pH 6.5, 0.2 LiSO4, and 30% (w/v) polyethylene glycol 400

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-B / Wavelength: 1.0331 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Oct 14, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0331 Å / Relative weight: 1
ReflectionResolution: 5.39→49.94 Å / Num. obs: 21811 / % possible obs: 96.3 % / Redundancy: 3.4 % / CC1/2: 0.99 / Rpim(I) all: 0.56 / Rsym value: 0.1 / Net I/σ(I): 8.9
Reflection shellResolution: 5.39→5.59 Å / Redundancy: 2.4 % / Mean I/σ(I) obs: 1 / Num. unique obs: 1941 / CC1/2: 0.589 / Rpim(I) all: 0.42 / Rsym value: 0.56 / % possible all: 86.4

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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,6OCB

5tg8

4we8

5kaq

6ocb


Resolution: 5.39→49.94 Å / SU ML: 1.09 / Cross valid method: THROUGHOUT / σ(F): 1.37 / Phase error: 40.78 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.342 1073 4.93 %
Rwork0.3041 20713 -
obs0.306 21786 95.88 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 404.55 Å2 / Biso mean: 312.0282 Å2 / Biso min: 213.29 Å2
Refinement stepCycle: final / Resolution: 5.39→49.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms31560 0 0 0 31560
Num. residues----4103
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A1221X-RAY DIFFRACTION0.035TORSIONAL
12C1221X-RAY DIFFRACTION0.035TORSIONAL
13G1221X-RAY DIFFRACTION0.035TORSIONAL
21B2571X-RAY DIFFRACTION0.035TORSIONAL
22D2571X-RAY DIFFRACTION0.035TORSIONAL
23I2571X-RAY DIFFRACTION0.035TORSIONAL
31E3018X-RAY DIFFRACTION0.035TORSIONAL
32J3018X-RAY DIFFRACTION0.035TORSIONAL
33L3018X-RAY DIFFRACTION0.035TORSIONAL
41F3075X-RAY DIFFRACTION0.035TORSIONAL
42H3075X-RAY DIFFRACTION0.035TORSIONAL
43K3075X-RAY DIFFRACTION0.035TORSIONAL
51N3015X-RAY DIFFRACTION0.035TORSIONAL
52Q3015X-RAY DIFFRACTION0.035TORSIONAL
53T3015X-RAY DIFFRACTION0.035TORSIONAL
61O3081X-RAY DIFFRACTION0.035TORSIONAL
62R3081X-RAY DIFFRACTION0.035TORSIONAL
63U3081X-RAY DIFFRACTION0.035TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 8

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
5.39-5.640.4011040.36682279238384
5.64-5.930.40891150.3542464257992
5.93-6.310.37891380.34652664280299
6.31-6.790.4161540.34712639279399
6.79-7.470.36141560.3482582273897
7.47-8.550.29871320.28642681281399
8.55-10.750.28471370.260627002837100
10.75-49.940.35661370.29622704284197

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