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- EMDB-29909: Structure of human NDS.3 Fab in complex with influenza virus neur... -

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Basic information

Entry
Database: EMDB / ID: EMD-29909
TitleStructure of human NDS.3 Fab in complex with influenza virus neuraminidase from A/Darwin/09/2021 (H3N2)
Map dataMap post-processed with DeepEMhancer
Sample
  • Complex: Influenza virus neuraminidase from A/Darwin/09/2021 (H3N2) in complex with Fab NDS.3
    • Protein or peptide: Neuraminidase
    • Protein or peptide: Fab NDS.3, heavy chain
    • Protein or peptide: Fab NDS.3, light chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Keywordsneuraminidase / antibody / influenza / VIRAL PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


exo-alpha-(2->3)-sialidase activity / exo-alpha-(2->6)-sialidase activity / exo-alpha-(2->8)-sialidase activity / exo-alpha-sialidase / viral budding from plasma membrane / carbohydrate metabolic process / host cell plasma membrane / virion membrane / membrane / metal ion binding
Similarity search - Function
Sialidase, Influenza viruses A/B / Glycoside hydrolase, family 34 / Neuraminidase / Sialidase superfamily
Similarity search - Domain/homology
Biological speciesHomo sapiens (human) / Influenza A virus
Methodsingle particle reconstruction / cryo EM / Resolution: 2.7 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_29909.png

Downloads & links

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Map

FileDownload / File: emd_29909.map.gz / Format: CCP4 / Size: 98.9 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: 0.07
Minimum - Maximum-0.027382385 - 1.6750889
Average (Standard dev.)0.0013318073 (±0.024987584)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions296296296
Spacing296296296
CellA=B=C: 328.56 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_29909_msk_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Additional map: Map automatically post-processed with Relion

Fileemd_29909_additional_1.map
AnnotationMap automatically post-processed with Relion
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Additional map: Map before post-processing

Fileemd_29909_additional_2.map
AnnotationMap before post-processing
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Half map: Half-map 1

Fileemd_29909_half_map_1.map
AnnotationHalf-map 1
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Histogram

Histogram (log scale)

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Half map: Half-map 2

Fileemd_29909_half_map_2.map
AnnotationHalf-map 2
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Sample components

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Entire : Influenza virus neuraminidase from A/Darwin/09/2021 (H3N2) in com...

EntireName: Influenza virus neuraminidase from A/Darwin/09/2021 (H3N2) in complex with Fab NDS.3
Components
  • Complex: Influenza virus neuraminidase from A/Darwin/09/2021 (H3N2) in complex with Fab NDS.3
    • Protein or peptide: Neuraminidase
    • Protein or peptide: Fab NDS.3, heavy chain
    • Protein or peptide: Fab NDS.3, light chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Influenza virus neuraminidase from A/Darwin/09/2021 (H3N2) in com...

SupramoleculeName: Influenza virus neuraminidase from A/Darwin/09/2021 (H3N2) in complex with Fab NDS.3
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 380 KDa

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Macromolecule #1: Neuraminidase

MacromoleculeName: Neuraminidase / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Influenza A virus / Strain: A/Darwin/09/2021 (H3N2)
Molecular weightTheoretical: 51.972344 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MEFGLSWIFL AAILKGVQCA DPHHHHHHHH SSSDRFDVDK LKQEIMTEIR REVSKMKQDI IEAIKVELNR GSLVPRGSGG EYRNWSKPQ CGITGFAPFS KDNSIRLSAG GDIWVTREPY VSCDLDKCYQ FALGQGTTLN NVHSNNTVSD RTPYRTLLMN E LGVPFHLG ...String:
MEFGLSWIFL AAILKGVQCA DPHHHHHHHH SSSDRFDVDK LKQEIMTEIR REVSKMKQDI IEAIKVELNR GSLVPRGSGG EYRNWSKPQ CGITGFAPFS KDNSIRLSAG GDIWVTREPY VSCDLDKCYQ FALGQGTTLN NVHSNNTVSD RTPYRTLLMN E LGVPFHLG TKQVCIAWSS SSCHDGKAWL HVCITGDDKN ATASFIYNGR LVDSVVSWSN DILRTQESEC VCINGTCTVV MT DGNATGK ADTKILFIEE GKIVHTSKLS GSAQHVEECS CYPRYPGVRC VCRDNWKGSN RPIIDINIKD HSIVSRYVCS GLV GDTPRK SDSSSSSHCL NPNNEKGDHG VKGWAFDDGN DVWMGRTINE TSRLGYETFK VVEGWSNPKS KLQINRQVIV DRGD RSGYS GIFSVEGKSC INRCFYVELI RGRKEETEVL WTSNSIVVFC GTSGTYGTGS WPDGANLSLM HI

UniProtKB: Neuraminidase

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Macromolecule #2: Fab NDS.3, heavy chain

MacromoleculeName: Fab NDS.3, heavy chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.20924 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EVQLVESGGG LVKPGGSLRL SCAASGFTFS DYSMTWIRQI PGKGLEWLSY TTSSGRPIFY ADSVKGRFTM SRDNAKMSVY LQMNSLRDA DSAVYYCARG DPHYIWGTYL DSWGPGTLVT VSSASTKGPS VFPLAPSSKS TSGGTAALGC LVKDYFPEPV T VSWNSGAL ...String:
EVQLVESGGG LVKPGGSLRL SCAASGFTFS DYSMTWIRQI PGKGLEWLSY TTSSGRPIFY ADSVKGRFTM SRDNAKMSVY LQMNSLRDA DSAVYYCARG DPHYIWGTYL DSWGPGTLVT VSSASTKGPS VFPLAPSSKS TSGGTAALGC LVKDYFPEPV T VSWNSGAL TSGVHTFPAV LQSSGLYSLS SVVTVPSSSL GTQTYICNVN HKPSNTKVDK KVEPKSCDK

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Macromolecule #3: Fab NDS.3, light chain

MacromoleculeName: Fab NDS.3, light chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 22.863139 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QSALTQPPSA SGSPGQSVTI SCTGTTSDFG DHNYVSWYQQ RPGEAPKLII YDVSKRPSGV PDRFSGSKSG NTASLTVSRL QADDEANYY CSSIEGSNTL LFGGGTKLTV LGQPKAAPSV TLFPPSSEEL QANKATLVCL ISDFYPGAVT VAWKADSSPV K AGVETTTP ...String:
QSALTQPPSA SGSPGQSVTI SCTGTTSDFG DHNYVSWYQQ RPGEAPKLII YDVSKRPSGV PDRFSGSKSG NTASLTVSRL QADDEANYY CSSIEGSNTL LFGGGTKLTV LGQPKAAPSV TLFPPSSEEL QANKATLVCL ISDFYPGAVT VAWKADSSPV K AGVETTTP SKQSNNKYAA SSYLSLTPEQ WKSHRSYSCQ VTHEGSTVEK TVAPTECS

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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: 3 / 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: 2.5 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: 1066523
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: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 247374
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-8gav:
Structure of human NDS.3 Fab in complex with influenza virus neuraminidase from A/Darwin/09/2021 (H3N2)

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