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- EMDB-29907: Structure of human NDS.1 Fab and 1G01 Fab in complex with influen... -

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Entry
Database: EMDB / ID: EMD-29907
TitleStructure of human NDS.1 Fab and 1G01 Fab in complex with influenza virus neuraminidase from A/Indiana/10/2011 (H3N2v); consensus map with only Fab 1G01 resolved
Map dataMap post-processed with DeepEMhancer
Sample
  • Complex: Influenza virus neuraminidase from A/Indiana/10/2011 (H3N2v) in complex with Fabs NDS.1 and 1G01
    • Protein or peptide: Vasodilator-stimulated phosphoprotein, Neuraminidase chimera
    • Protein or peptide: Fab 1G01, heavy chain
    • Protein or peptide: Fab 1G01, light chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Keywordsneuraminidase / antibody / influenza / VIRAL PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


profilin binding / Cell-extracellular matrix interactions / Signaling by ROBO receptors / actin polymerization or depolymerization / filopodium membrane / exo-alpha-(2->3)-sialidase activity / exo-alpha-(2->6)-sialidase activity / exo-alpha-(2->8)-sialidase activity / positive regulation of actin filament polymerization / exo-alpha-sialidase ...profilin binding / Cell-extracellular matrix interactions / Signaling by ROBO receptors / actin polymerization or depolymerization / filopodium membrane / exo-alpha-(2->3)-sialidase activity / exo-alpha-(2->6)-sialidase activity / exo-alpha-(2->8)-sialidase activity / positive regulation of actin filament polymerization / exo-alpha-sialidase / lamellipodium membrane / Generation of second messenger molecules / bicellular tight junction / viral budding from plasma membrane / neural tube closure / axon guidance / SH3 domain binding / actin cytoskeleton / actin binding / actin cytoskeleton organization / protein homotetramerization / carbohydrate metabolic process / cadherin binding / focal adhesion / host cell plasma membrane / virion membrane / extracellular exosome / membrane / metal ion binding / plasma membrane / cytosol
Similarity search - Function
Vasodilator-stimulated phosphoprotein/ENA/VASP-like / VASP tetramerisation / VASP tetramerisation domain superfamily / VASP tetramerisation domain / WH1/EVH1 domain / WH1 domain / WH1 domain profile. / WASP homology region 1 / Sialidase, Influenza viruses A/B / Glycoside hydrolase, family 34 ...Vasodilator-stimulated phosphoprotein/ENA/VASP-like / VASP tetramerisation / VASP tetramerisation domain superfamily / VASP tetramerisation domain / WH1/EVH1 domain / WH1 domain / WH1 domain profile. / WASP homology region 1 / Sialidase, Influenza viruses A/B / Glycoside hydrolase, family 34 / Neuraminidase / Sialidase superfamily / PH-like domain superfamily
Similarity search - Domain/homology
Neuraminidase / Vasodilator-stimulated phosphoprotein
Similarity search - Component
Biological speciesHomo sapiens (human) / Influenza A virus (A/Indiana/10/2011(H3N2))
Methodsingle particle reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsTsybovsky Y / Lederhofer J / Kwong PD / Kanekiyo M
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Immunity / Year: 2024
Title: Protective human monoclonal antibodies target conserved sites of vulnerability on the underside of influenza virus neuraminidase.
Authors: Julia Lederhofer / Yaroslav Tsybovsky / Lam Nguyen / Julie E Raab / Adrian Creanga / Tyler Stephens / Rebecca A Gillespie / Hubza Z Syeda / Brian E Fisher / Michelle Skertic / Christina Yap ...Authors: Julia Lederhofer / Yaroslav Tsybovsky / Lam Nguyen / Julie E Raab / Adrian Creanga / Tyler Stephens / Rebecca A Gillespie / Hubza Z Syeda / Brian E Fisher / Michelle Skertic / Christina Yap / Andrew J Schaub / Reda Rawi / Peter D Kwong / Barney S Graham / Adrian B McDermott / Sarah F Andrews / Neil P King / Masaru Kanekiyo /
Abstract: Continuously evolving influenza viruses cause seasonal epidemics and pose global pandemic threats. Although viral neuraminidase (NA) is an effective drug and vaccine target, our understanding of the ...Continuously evolving influenza viruses cause seasonal epidemics and pose global pandemic threats. Although viral neuraminidase (NA) is an effective drug and vaccine target, our understanding of the NA antigenic landscape still remains incomplete. Here, we describe NA-specific human antibodies that target the underside of the NA globular head domain, inhibit viral propagation of a wide range of human H3N2, swine-origin variant H3N2, and H2N2 viruses, and confer both pre- and post-exposure protection against lethal H3N2 infection in mice. Cryo-EM structures of two such antibodies in complex with NA reveal non-overlapping epitopes covering the underside of the NA head. These sites are highly conserved among N2 NAs yet inaccessible unless the NA head tilts or dissociates. Our findings help guide the development of effective countermeasures against ever-changing influenza viruses by identifying hidden conserved sites of vulnerability on the NA underside.
History
DepositionFeb 23, 2023-
Header (metadata) releaseFeb 28, 2024-
Map releaseFeb 28, 2024-
UpdateApr 24, 2024-
Current statusApr 24, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_29907.png

Downloads & links

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Map

FileDownload / File: emd_29907.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationMap post-processed with DeepEMhancer
Voxel sizeX=Y=Z: 1.11 Å
Density
Contour LevelBy AUTHOR: 0.6
Minimum - Maximum-0.023448206 - 1.6800616
Average (Standard dev.)0.0013414347 (±0.024782673)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 355.2 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_29907_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: Map before post-processing

Fileemd_29907_additional_1.map
AnnotationMap before post-processing
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Additional map: Map post-processed automatically in Relion

Fileemd_29907_additional_2.map
AnnotationMap post-processed automatically in Relion
Projections & Slices
AxesZYX

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Histogram

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Half map: Half-map 2

Fileemd_29907_half_map_1.map
AnnotationHalf-map 2
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half-map 1

Fileemd_29907_half_map_2.map
AnnotationHalf-map 1
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Sample components

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Entire : Influenza virus neuraminidase from A/Indiana/10/2011 (H3N2v) in c...

EntireName: Influenza virus neuraminidase from A/Indiana/10/2011 (H3N2v) in complex with Fabs NDS.1 and 1G01
Components
  • Complex: Influenza virus neuraminidase from A/Indiana/10/2011 (H3N2v) in complex with Fabs NDS.1 and 1G01
    • Protein or peptide: Vasodilator-stimulated phosphoprotein, Neuraminidase chimera
    • Protein or peptide: Fab 1G01, heavy chain
    • Protein or peptide: Fab 1G01, light chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Influenza virus neuraminidase from A/Indiana/10/2011 (H3N2v) in c...

SupramoleculeName: Influenza virus neuraminidase from A/Indiana/10/2011 (H3N2v) in complex with Fabs NDS.1 and 1G01
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 580 KDa

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Macromolecule #1: Vasodilator-stimulated phosphoprotein, Neuraminidase chimera

MacromoleculeName: Vasodilator-stimulated phosphoprotein, Neuraminidase chimera
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: exo-alpha-sialidase
Source (natural)Organism: Influenza A virus (A/Indiana/10/2011(H3N2)) / Strain: A/Indiana/10/2011(H3N2)
Molecular weightTheoretical: 51.799113 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MEFGLSWIFL AAILKGVQCA DPHHHHHHSS SDYSDLQRVK QELLEEVKKE LQKVKEEIIE AFVQELRKRG SLVPRGSGGE YRNWSKPQC NITGFAPFSK DNSIRLSAGG DIWVTREPYV SCDPDKCYQF ALGQGTTLNN GHSNNTVHDR TPYRTLLMNE L GVPFHLGT ...String:
MEFGLSWIFL AAILKGVQCA DPHHHHHHSS SDYSDLQRVK QELLEEVKKE LQKVKEEIIE AFVQELRKRG SLVPRGSGGE YRNWSKPQC NITGFAPFSK DNSIRLSAGG DIWVTREPYV SCDPDKCYQF ALGQGTTLNN GHSNNTVHDR TPYRTLLMNE L GVPFHLGT RQVCMAWSSS SCHDGKAWLH VCITGNDNNA TASFIYNGRL VDSIGSWSKN ILRTQESECV CINGTCTVVM TD GSASGKA DTKILFVEEG KIVHISTLSG SAQHVEECSC YPRFPGVRCV CRDNWKGSNR PIVDINVKNY SIVSSYVCSG LVG DTPRKS DSVSSSYCLD PNNEKGGHGV KGWAFDDGND VWMGRTINET LRLGYETFKV IEGWSKANSK LQTNRQVIVE KGDR SGYSG IFSVEGKSCI NRCFYVELIR GRKEETKVWW TSNSIVVFCG TSGTYGTGSW PDGADINLMP I

UniProtKB: Vasodilator-stimulated phosphoprotein, Neuraminidase

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Macromolecule #2: Fab 1G01, heavy chain

MacromoleculeName: Fab 1G01, heavy chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 25.981021 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DEVQLVESGG RALRPGGSLR LSCAASGFKF DDYAMSWVRQ VPGKGLEFVS GLNWNGDITA YTDSVKGRFT VSRDNAKNSL YLHINSPKP EDTALYYCAR TSSWGDYTRG PEPKITWYFD LWGRGTLVTV SSASTKGPSV FPLAPSSKST SGGTAALGCL V KDYFPEPV ...String:
DEVQLVESGG RALRPGGSLR LSCAASGFKF DDYAMSWVRQ VPGKGLEFVS GLNWNGDITA YTDSVKGRFT VSRDNAKNSL YLHINSPKP EDTALYYCAR TSSWGDYTRG PEPKITWYFD LWGRGTLVTV SSASTKGPSV FPLAPSSKST SGGTAALGCL V KDYFPEPV TVSWNSGALT SGVHTFPAVL QSSGLYSLSS VVTVPSSSLG TQTYICNVNH KPSNTKVDKR VEPKSCHHHH HH

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Macromolecule #3: Fab 1G01, light chain

MacromoleculeName: Fab 1G01, light chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.677273 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DDIQLTQSPS FLSASVGDRI TITCRASQGI DGYLAWYQQR PGKAPNLLIY AASLLQSGVP SRFSGSGYGT EFTLTISSLQ PEDFATYYC QHLDSYPLFT FGPGTKVDIK RTVAAPSVFI FPPSDEQLKS GTASVVCLLN NFYPREAKVQ WKVDNALQSG N SQESVTEQ ...String:
DDIQLTQSPS FLSASVGDRI TITCRASQGI DGYLAWYQQR PGKAPNLLIY AASLLQSGVP SRFSGSGYGT EFTLTISSLQ PEDFATYYC QHLDSYPLFT FGPGTKVDIK RTVAAPSVFI FPPSDEQLKS GTASVVCLLN NFYPREAKVQ WKVDNALQSG N SQESVTEQ DSKDSTYSLS STLTLSKADY EKHKVYACEV THQGLSSPVT KSFNRGEC

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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: 4 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

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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

Concentration0.15 mg/mL
BufferpH: 7
VitrificationCryogen name: NITROGEN

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 3.0 µm / Nominal defocus min: 1.0 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average electron dose: 40.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1109902
Startup modelType of model: NONE
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionApplied symmetry - Point group: C4 (4 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 62699
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelChain - Source name: SwissModel / Chain - Initial model type: in silico model
RefinementSpace: REAL / Protocol: BACKBONE TRACE
Output model

PDB-8gat:
Structure of human NDS.1 Fab and 1G01 Fab in complex with influenza virus neuraminidase from A/Indiana/10/2011 (H3N2v), based on consensus cryo-EM map with only Fab 1G01 resolved

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