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- PDB-9onz: Influenza A Virus Group 2 Hemagglutinin (H7, Strain SH13) in Comp... -

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Basic information

Entry
Database: PDB / ID: 9onz
TitleInfluenza A Virus Group 2 Hemagglutinin (H7, Strain SH13) in Complex with the Potent Small-Molecule Entry Inhibitor SA-67
Components
  • Hemagglutinin HA1
  • Hemagglutinin HA2
KeywordsVIRAL PROTEIN/INHIBITOR / Influenza A Virus / Hemagglutinin / Complex / Small-Molecule Inhibitor / Entry / SA-67 / VIRAL PROTEIN-INHIBITOR 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
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.77 Å
AuthorsXu, Y. / Xu, K.
Funding support United States, 1items
OrganizationGrant numberCountry
Not funded United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2025
Title: Mechanistic insights into the small-molecule inhibition of influenza A virus entry.
Authors: Yan Xu / Varada Anirudhan / Irina N Gaisina / Haijuan Du / Saad Alqarni / Terry W Moore / Michael Caffrey / Balaji Manicassamy / Tongqing Zhou / Lijun Rong / Kai Xu /
Abstract: Influenza A virus (IAV) is a zoonotic pathogen responsible for seasonal and pandemic flu. The extensive genetic and antigenic diversity within and between IAV phylogenetic groups presents major ...Influenza A virus (IAV) is a zoonotic pathogen responsible for seasonal and pandemic flu. The extensive genetic and antigenic diversity within and between IAV phylogenetic groups presents major challenges for developing universal vaccines and broad-spectrum antiviral therapies. Current interventions provide limited protection due to the virus's high mutation rate and capacity for immune evasion. Recent advancements in viral hemagglutinin (HA)-targeting small-molecule entry inhibitors offer a promising avenue to overcome these limitations. Here, we present structural and functional analyses of two group 2 HA-specific small-molecule inhibitors recently identified by our team. Cryogenic electron microscopy (cryo-EM) structures revealed that these inhibitors bind a conserved pocket within the HA stalk, likely interfering with the conformational rearrangements necessary for membrane fusion and viral entry. Structure-guided mutagenesis confirmed the critical roles of key interacting residues and uncovered distinct resistance profiles between the two compounds, as well as in comparison to Arbidol, a previously reported HA inhibitor. Notably, our structural analysis highlights intrinsic barriers to achieving cross-group inhibition with current small-molecule designs. To address this, we propose an alternative strategy for broadening antiviral coverage. Together, these findings provide mechanistic insights into IAV entry inhibition and a foundation for the rational design of next-generation anti-influenza therapeutics.
History
DepositionMay 15, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 16, 2025Provider: repository / Type: Initial release
Revision 1.0Jul 16, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jul 16, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.0Jul 16, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jul 16, 2025Data content type: Mask / Part number: 1 / Data content type: Mask / Provider: repository / Type: Initial release
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Revision 1.1Aug 27, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Hemagglutinin HA1
B: Hemagglutinin HA1
C: Hemagglutinin HA1
D: Hemagglutinin HA2
E: Hemagglutinin HA2
F: Hemagglutinin HA2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)173,81321
Polymers169,1316
Non-polymers4,68215
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Hemagglutinin HA1


Mass: 36526.305 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Influenza A virus / Gene: HA / Production host: Homo sapiens (human) / References: UniProt: A0A067Y6L0
#2: Protein Hemagglutinin HA2


Mass: 19850.803 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Influenza A virus / Gene: HA / Production host: Homo sapiens (human) / References: UniProt: A0A067Y6L0
#3: Polysaccharide oligosaccharide


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
#4: 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.: 9 / 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
#5: Chemical ChemComp-A1CC2 / (4R)-N-cyclohexyl-2-(4-fluorophenyl)imidazo[1,2-a]pyrimidin-3-amine


Mass: 310.369 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C18H19FN4 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
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: Influenza A virus / Type: VIRUS / Entity ID: #1-#2 / Source: RECOMBINANT
Source (natural)Organism: Influenza A virus
Source (recombinant)Organism: Homo sapiens (human)
Details of virusEmpty: YES / Enveloped: YES / Isolate: STRAIN / Type: VIRION
Buffer solutionpH: 7.2 / Details: 5mM HEPES buffer pH7.2, 150nM NaCl
SpecimenConc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: 1mg/ml in HBS buffer, purfied from HEK293 recombinant expression and purified with NiNTA resin via Hisx6 tag
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 273 K

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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: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 81000 X / Nominal defocus max: 3000 nm / Nominal defocus min: 500 nm
Specimen holderCryogen: NITROGEN
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOCONTINUUM (6k x 4k)

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
4cryoSPARCCTF correction
7UCSF ChimeraXmodel fitting
12cryoSPARC3D reconstruction
13PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 6403039
SymmetryPoint symmetry: C3 (3 fold cyclic)
3D reconstructionResolution: 2.77 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 155278 / Symmetry type: POINT
Atomic model buildingB value: 112 / Protocol: OTHER
Atomic model buildingPDB-ID: 8TNL

8tnl


Accession code: 8TNL / Details: complete model of PDB 8TNL / Source name: PDB / Type: experimental model

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