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- PDB-8gat: Structure of human NDS.1 Fab and 1G01 Fab in complex with influen... -

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Basic information

Entry
Database: PDB / ID: 8gat
TitleStructure 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
Components
  • Fab 1G01, heavy chain
  • Fab 1G01, light chain
  • Vasodilator-stimulated phosphoprotein, Neuraminidase chimera
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / neuraminidase / antibody / influenza / VIRAL PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


profilin binding / Signaling by ROBO receptors / Cell-extracellular matrix interactions / 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 / Signaling by ROBO receptors / Cell-extracellular matrix interactions / 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
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsTsybovsky, Y. / Lederhofer, J. / Kwong, P.D. / Kanekiyo, M.
Funding support1items
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, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 28, 2024Provider: repository / Type: Initial release
Revision 1.1Mar 13, 2024Group: 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.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Mar 27, 2024Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Apr 24, 2024Group: Refinement description / Category: em_3d_fitting / em_3d_fitting_list / Item: _em_3d_fitting_list.3d_fitting_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Vasodilator-stimulated phosphoprotein, Neuraminidase chimera
M: Fab 1G01, heavy chain
N: Fab 1G01, light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)102,3427
Polymers101,4573
Non-polymers8854
Water0
1
A: Vasodilator-stimulated phosphoprotein, Neuraminidase chimera
M: Fab 1G01, heavy chain
N: Fab 1G01, light chain
hetero molecules

A: Vasodilator-stimulated phosphoprotein, Neuraminidase chimera
M: Fab 1G01, heavy chain
N: Fab 1G01, light chain
hetero molecules

A: Vasodilator-stimulated phosphoprotein, Neuraminidase chimera
M: Fab 1G01, heavy chain
N: Fab 1G01, light chain
hetero molecules

A: Vasodilator-stimulated phosphoprotein, Neuraminidase chimera
M: Fab 1G01, heavy chain
N: Fab 1G01, light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)409,36928
Polymers405,83012
Non-polymers3,53916
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation3
2


  • Idetical with deposited unit
  • point asymmetric unit
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3


  • Idetical with deposited unit in distinct coordinate
  • point asymmetric unit, std point frame
TypeNameSymmetry operationNumber
transform to point frame1
SymmetryPoint symmetry: (Schoenflies symbol: C4 (4 fold cyclic))

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Components

#1: Protein Vasodilator-stimulated phosphoprotein, Neuraminidase chimera / VASP


Mass: 51799.113 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Influenza A virus (A/Indiana/10/2011(H3N2))
Gene: VASP, NA, L998_47825gpNA / Strain: A/Indiana/10/2011(H3N2) / Cell line (production host): Expi293 / Production host: Homo sapiens (human)
References: UniProt: P50552, UniProt: G9LQ08, exo-alpha-sialidase
#2: Antibody Fab 1G01, heavy chain


Mass: 25981.021 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): Expi293 / Production host: Homo sapiens (human)
#3: Antibody Fab 1G01, light chain


Mass: 23677.273 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): Expi293 / Production host: Homo sapiens (human)
#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 / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 4 / 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
Has ligand of interestN

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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 virus neuraminidase from A/Indiana/10/2011 (H3N2v) in complex with Fabs NDS.1 and 1G01
Type: COMPLEX / Entity ID: #1-#3 / Source: MULTIPLE SOURCES
Molecular weightValue: 0.580 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Cell: Expi293
Buffer solutionpH: 7
SpecimenConc.: 0.15 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: NITROGEN

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 3000 nm / Nominal defocus min: 1000 nm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 40 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.12_2829: / Classification: refinement
EM softwareName: SerialEM / Version: 4.09 / Category: image acquisition
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 1109902
SymmetryPoint symmetry: C4 (4 fold cyclic)
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 62699 / Symmetry type: POINT
Atomic model buildingProtocol: BACKBONE TRACE / Space: REAL
Atomic model buildingSource name: SwissModel / Type: in silico model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0065071
ELECTRON MICROSCOPYf_angle_d0.9386905
ELECTRON MICROSCOPYf_dihedral_angle_d10.2882948
ELECTRON MICROSCOPYf_chiral_restr0.056762
ELECTRON MICROSCOPYf_plane_restr0.007875

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