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- PDB-8zyk: Crystal structure of hemagglutinin from HN/4-10 H3N8 influenza vi... -

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Basic information

Entry
Database: PDB / ID: 8zyk
TitleCrystal structure of hemagglutinin from HN/4-10 H3N8 influenza virus S228 mutant
Components(Hemagglutinin) x 2
KeywordsVIRAL PROTEIN / hemagglutinin
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
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.01 Å
AuthorsHao, T.J. / Chai, Y. / Song, H. / Gao, G.F.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: J Virol / Year: 2025
Title: Structural basis of receptor-binding adaptation of human-infecting H3N8 influenza A virus.
Authors: Tianjiao Hao / Yufeng Xie / Yan Chai / Wei Zhang / Di Zhang / Jianxun Qi / Yi Shi / Hao Song / George F Gao /
Abstract: Recent avian-origin H3N8 influenza A virus (IAV) that have infected humans pose a potential public health concern. Alterations in the viral surface glycoprotein, hemagglutinin (HA), are typically ...Recent avian-origin H3N8 influenza A virus (IAV) that have infected humans pose a potential public health concern. Alterations in the viral surface glycoprotein, hemagglutinin (HA), are typically required for IAVs to cross the species barrier for adaptation to a new host, but whether H3N8 has adapted to infect humans remains elusive. The observation of a degenerative codon in position 228 of HA in human H3N8 A/Henan/4-10/2022 protein sequence, which could be residue G or S, suggests a dynamic viral adaptation for human infection. Previously, we found this human-isolated virus has shown the ability to transmit between ferrets via respiratory droplets, with the HA-G228S substitution mutation emerging as a critical determinant for the airborne transmission of the virus in ferrets. Here, we investigated the receptor-binding properties of these two H3N8 HAs. Our results showed H3N8 HAs have dual receptor-binding properties with a preference for avian receptor binding, and G228S slightly increased binding to human receptors. Cryo-electron microscopy structures of the two H3N8 HAs with avian and human receptor analogs revealed the basis for dual receptor binding. Mutagenesis studies reveal that the Q226L mutation shifts H3N8 HA's receptor preference from avian to human, while the G228S substitution enhances binding to both receptor types. H3N8 exhibits distinct antigenic sites compared to H3N2, prompting concerns regarding vaccine efficacy. These findings suggest that the current H3N8 human isolates are yet to adapt for efficient human-to-human transmission and further continuous surveillance should be implemented.IMPORTANCEInfluenza virus transmission remains a public health concern currently. H3N8 subtype influenza A viruses infect humans and their HAs acquire the ability to bind to both human and avian receptors, posing a threat to human health. We have solved and analyzed the structural basis of dual receptor binding of recently human-infecting H3N8 HA, and we demonstrate that the G228S enhances human receptor binding and adaptation. We also found that HN/4-10 H3N8 HA has distinct antigenic sites, which challenges vaccine efficacy. Taken together, our work is critical to the prevention and control of human H3 influenza virus infection.
History
DepositionJun 18, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Feb 19, 2025Provider: repository / Type: Initial release
Revision 1.1Aug 13, 2025Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Hemagglutinin
R: Hemagglutinin
B: Hemagglutinin
S: Hemagglutinin
C: Hemagglutinin
T: Hemagglutinin
D: Hemagglutinin
U: Hemagglutinin
E: Hemagglutinin
V: Hemagglutinin
F: Hemagglutinin
W: Hemagglutinin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)349,99230
Polymers342,15412
Non-polymers7,83818
Water00
1
A: Hemagglutinin
R: Hemagglutinin
B: Hemagglutinin
S: Hemagglutinin
C: Hemagglutinin
T: Hemagglutinin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)175,31916
Polymers171,0776
Non-polymers4,24210
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
D: Hemagglutinin
U: Hemagglutinin
E: Hemagglutinin
V: Hemagglutinin
F: Hemagglutinin
W: Hemagglutinin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)174,67314
Polymers171,0776
Non-polymers3,5968
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)136.829, 167.321, 206.841
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

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Protein , 2 types, 12 molecules ABCDEFRSTUVW

#1: Protein
Hemagglutinin


Mass: 36571.055 Da / Num. of mol.: 6 / Mutation: S228
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Influenza A virus / Production host: Spodoptera frugiperda (fall armyworm)
#2: Protein
Hemagglutinin


Mass: 20454.584 Da / Num. of mol.: 6 / Fragment: HA2 / Mutation: S228
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Influenza A virus / Gene: HA / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: A0A8K0YBM5

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Sugars , 6 types, 18 molecules

#3: 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-Glycam 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
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}}LINUCSPDB-CARE
#4: 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.: 5
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-Glycam 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
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#5: Polysaccharide alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2- ...alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 910.823 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3[DManpa1-6]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/3,5,4/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3-3/a4-b1_b4-c1_c3-d1_c6-e1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}[(6+1)][a-D-Manp]{}}}}}LINUCSPDB-CARE
#6: Polysaccharide alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1- ...alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 748.682 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-6DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/3,4,3/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3/a4-b1_b4-c1_c6-d1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(6+1)][a-D-Manp]{}}}}}LINUCSPDB-CARE
#7: Polysaccharide alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1- ...alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 748.682 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/3,4,3/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3/a4-b1_b4-c1_c3-d1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}}}}}LINUCSPDB-CARE
#8: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Details

Has ligand of interestN
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: 3.46 Å3/Da / Density % sol: 64.46 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop
Details: 28% v/v 2-Propanol, 0.1 M BIS-TRIS pH 6.5, 3% v/v Polyethylene glycol 200

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 1.03961 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Oct 24, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.03961 Å / Relative weight: 1
ReflectionResolution: 3→50 Å / Num. obs: 93878 / % possible obs: 96.18 % / Redundancy: 10 % / Biso Wilson estimate: 61.87 Å2 / CC1/2: 0.748 / Net I/σ(I): 8.3
Reflection shellResolution: 3→3.11 Å / Rmerge(I) obs: 1.251 / Num. unique obs: 93878 / CC1/2: 0.692

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
HKL-2000data reduction
HKL-2000data scaling
PHENIX1.19.2_4158phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.01→28.53 Å / SU ML: 0.4243 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 29.1833
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2779 4449 4.9 %
Rwork0.238 86405 -
obs0.2399 90854 96.18 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 56.89 Å2
Refinement stepCycle: LAST / Resolution: 3.01→28.53 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms23112 0 516 0 23628
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.002324114
X-RAY DIFFRACTIONf_angle_d0.481232686
X-RAY DIFFRACTIONf_chiral_restr0.04143679
X-RAY DIFFRACTIONf_plane_restr0.00324242
X-RAY DIFFRACTIONf_dihedral_angle_d4.83213440
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.01-3.040.3279870.30851662X-RAY DIFFRACTION55.84
3.04-3.080.33991080.30912252X-RAY DIFFRACTION76.47
3.08-3.120.3531050.30422492X-RAY DIFFRACTION83.13
3.12-3.160.34311180.29332656X-RAY DIFFRACTION89.2
3.16-3.20.33141400.30562791X-RAY DIFFRACTION94.46
3.2-3.240.38471510.2972862X-RAY DIFFRACTION96.88
3.24-3.290.34381480.28782933X-RAY DIFFRACTION97.62
3.29-3.340.3191170.30112948X-RAY DIFFRACTION98.55
3.34-3.390.34721550.2952913X-RAY DIFFRACTION99.32
3.39-3.440.36841470.32122980X-RAY DIFFRACTION99.33
3.44-3.50.34881570.3232917X-RAY DIFFRACTION98.78
3.5-3.570.3191450.28152972X-RAY DIFFRACTION99.62
3.57-3.640.27781540.26292960X-RAY DIFFRACTION99.84
3.64-3.710.34491540.32142954X-RAY DIFFRACTION99.2
3.71-3.790.37921530.2762973X-RAY DIFFRACTION99.81
3.79-3.880.31021660.27762935X-RAY DIFFRACTION99.77
3.88-3.980.37311810.30142923X-RAY DIFFRACTION98.45
3.98-4.080.28291560.24362969X-RAY DIFFRACTION99.94
4.08-4.20.26671680.21762969X-RAY DIFFRACTION99.84
4.2-4.340.25741480.19972997X-RAY DIFFRACTION99.84
4.34-4.490.2371290.20323012X-RAY DIFFRACTION99.87
4.49-4.670.22561830.20092970X-RAY DIFFRACTION99.94
4.67-4.880.2481560.19292987X-RAY DIFFRACTION99.97
4.88-5.140.2341650.19552993X-RAY DIFFRACTION99.84
5.14-5.460.24851550.19793011X-RAY DIFFRACTION99.87
5.46-5.880.25811460.20693034X-RAY DIFFRACTION99.97
5.88-6.460.24821590.2053052X-RAY DIFFRACTION99.94
6.46-7.380.21831770.20893025X-RAY DIFFRACTION100
7.38-9.250.21561620.18753074X-RAY DIFFRACTION99.85
9.25-28.530.20851590.19183189X-RAY DIFFRACTION99.14

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