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- EMDB-70658: Influenza A Virus Group 2 Hemagglutinin (H7, Strain SH13) in Comp... -

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Basic information

Entry
Database: EMDB / ID: EMD-70658
TitleInfluenza A Virus Group 2 Hemagglutinin (H7, Strain SH13) in Complex with a Potent Small-Molecule Entry Inhibitor ING-16-36
Map data
Sample
  • Virus: Influenza A virus
    • Protein or peptide: Hemagglutinin HA1
    • Protein or peptide: Hemagglutinin HA2
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: (2M,4S)-2-(2-chloropyridin-4-yl)-N-cyclohexyl-5,7-dimethylimidazo[1,2-a]pyrimidin-3-amine
KeywordsInfluenza A Virus / Hemagglutinin / Complex / Small-Molecule Inhibitor / Entry / ING-16-36 / 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
Methodsingle particle reconstruction / cryo EM / Resolution: 2.76 Å
AuthorsXu Y / Xu K
Funding support United States, 1 items
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, 2025-
Header (metadata) releaseJul 16, 2025-
Map releaseJul 16, 2025-
UpdateAug 27, 2025-
Current statusAug 27, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_70658.png

Downloads & links

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Map

FileDownload / File: emd_70658.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.9 Å/pix.
x 360 pix.
= 323.64 Å		0.9 Å/pix.
x 360 pix.
= 323.64 Å		0.9 Å/pix.
x 360 pix.
= 323.64 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.899 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.31223744 - 0.7142657
Average (Standard dev.)0.00093129184 (±0.0146459965)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 323.63998 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_70658_msk_1.map
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Half map: #1

Fileemd_70658_half_map_1.map
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Half map: #2

Fileemd_70658_half_map_2.map
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Sample components

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Entire : Influenza A virus

EntireName: Influenza A virus
Components
  • Virus: Influenza A virus
    • Protein or peptide: Hemagglutinin HA1
    • Protein or peptide: Hemagglutinin HA2
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: (2M,4S)-2-(2-chloropyridin-4-yl)-N-cyclohexyl-5,7-dimethylimidazo[1,2-a]pyrimidin-3-amine

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Supramolecule #1: Influenza A virus

SupramoleculeName: Influenza A virus / type: virus / ID: 1 / Parent: 0 / Macromolecule list: #1-#2 / NCBI-ID: 11320 / Sci species name: Influenza A virus / Virus type: VIRION / Virus isolate: STRAIN / Virus enveloped: Yes / Virus empty: Yes

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Macromolecule #1: Hemagglutinin HA1

MacromoleculeName: Hemagglutinin HA1 / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Influenza A virus
Molecular weightTheoretical: 36.809652 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MNTQILVFAL IAIIPTNADK ICLGHHAVSN GTKVNTLCER GVEVVNATET VERTNIPRIC SKGKRTVDLG QCGLLGTITG PPQCDQFLE FSADLIIERR EGSDVCYPGK FVNEEALRQI LRESGGIDKE AMGFTYSGIR TNGATSSCRR SGSSFYAEMK W LLSNTDNA ...String:
MNTQILVFAL IAIIPTNADK ICLGHHAVSN GTKVNTLCER GVEVVNATET VERTNIPRIC SKGKRTVDLG QCGLLGTITG PPQCDQFLE FSADLIIERR EGSDVCYPGK FVNEEALRQI LRESGGIDKE AMGFTYSGIR TNGATSSCRR SGSSFYAEMK W LLSNTDNA AFPQMTKSYK NTRKNPALIV WGIHHSGSTA EQTKLYGSGN KLVTVGSSNY QQSFVPSPGA RTQVNGQSGR ID FHWLMLN PNDTVTFSFN GAFIAPDRAS FLRGKSMGIQ SGVQVDADCE GDCYYSGGTI ISNLPFQNID SRAVGKCPRY VKQ RSLLLA TGMKNVPEIP KG

UniProtKB: Hemagglutinin

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Macromolecule #2: Hemagglutinin HA2

MacromoleculeName: Hemagglutinin HA2 / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Influenza A virus
Molecular weightTheoretical: 19.850803 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
GLFGAIAGFI ENGWEGLIDG WYGFRHQNAQ GEGTAADYKS TQSAIDCITG KLNRLIEKTN QQFELIDNEF TEVEKQIGNV INWTRDSIT EVWSYNAELL VAMENQHTID LADSEMDKLY ERVKRQLREN AEEDGTGCFE IFHKCDDDCM ASIRNNTYDH S KYREEAMQ NRIQ

UniProtKB: Hemagglutinin

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Macromolecule #4: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 4 / Number of copies: 9 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Macromolecule #5: (2M,4S)-2-(2-chloropyridin-4-yl)-N-cyclohexyl-5,7-dimethylimidazo...

MacromoleculeName: (2M,4S)-2-(2-chloropyridin-4-yl)-N-cyclohexyl-5,7-dimethylimidazo[1,2-a]pyrimidin-3-amine
type: ligand / ID: 5 / Number of copies: 3 / Formula: A1CC3
Molecular weightTheoretical: 355.864 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration1 mg/mL
BufferpH: 7.2 / Details: 5mM HEPES buffer pH7.2, 150nM NaCl
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 273 K / Instrument: FEI VITROBOT MARK IV
Details1mg/ml in HBS buffer, purfied from HEK293 recombinant expression and purified with NiNTA resin via Hisx6 tag

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOCONTINUUM (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.0 µm / Nominal defocus min: 0.5 µm / Nominal magnification: 81000
Sample stageCooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 4709508
CTF correctionSoftware - Name: cryoSPARC / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.76 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 195885
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE
Final 3D classificationNumber classes: 3

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Atomic model buiding 1

Initial modelPDB ID:

8tnl


Chain - Source name: PDB / Chain - Initial model type: experimental model / Details: complete model of PDB 8TNL
RefinementProtocol: OTHER / Overall B value: 112
Output model

PDB-9oo1:
Influenza A Virus Group 2 Hemagglutinin (H7, Strain SH13) in Complex with a Potent Small-Molecule Entry Inhibitor ING-16-36

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