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- EMDB-41715: Lassa GPC (strain Josiah) bound to rabbit polyclonal fusion-pepti... -

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Basic information

Entry
Database: EMDB / ID: EMD-41715
TitleLassa GPC (strain Josiah) bound to rabbit polyclonal fusion-peptide-targeting antibody FP-1
Map data
Sample
  • Complex: Heterotrimeric Lassa GPC bound to heterodimeric rabbit polyclonal fusion-peptide-targeting antibody FP-1
    • Complex: Glycoprotein G1, Glycoprotein G2, 2-dehydro-3-deoxyphosphogluconate aldolase/4-hydroxy-2-oxoglutarate aldolase fusion protein
      • Protein or peptide: Glycoprotein GP1
      • Protein or peptide: Glycoprotein GP2
    • Complex: Polyclonal antibody FP-1 heavy chain, Polyclonal antibody FP-1 light chain
      • Protein or peptide: Polyclonal Fv heavy chain
      • Protein or peptide: Polyclonal Fv light chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsLassa virus glycoprotein complex / GPC / immune complex / antibody / polyclonal antibody / base antibody / VIRAL PROTEIN / VIRAL PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


D-galactonate catabolic process / 2-dehydro-3-deoxy-6-phosphogalactonate aldolase activity / host cell Golgi membrane / receptor-mediated endocytosis of virus by host cell / host cell endoplasmic reticulum membrane / fusion of virus membrane with host endosome membrane / viral envelope / virion attachment to host cell / host cell plasma membrane / virion membrane ...D-galactonate catabolic process / 2-dehydro-3-deoxy-6-phosphogalactonate aldolase activity / host cell Golgi membrane / receptor-mediated endocytosis of virus by host cell / host cell endoplasmic reticulum membrane / fusion of virus membrane with host endosome membrane / viral envelope / virion attachment to host cell / host cell plasma membrane / virion membrane / metal ion binding / membrane
Similarity search - Function
KDPG/KHG aldolase / KDPG and KHG aldolase / Arenavirus glycoprotein, zinc binding domain / Arenavirus glycoprotein / Arenavirus glycoprotein / Aldolase-type TIM barrel
Similarity search - Domain/homology
Pre-glycoprotein polyprotein GP complex / 2-dehydro-3-deoxyphosphogluconate aldolase/4-hydroxy-2-oxoglutarate aldolase
Similarity search - Component
Biological speciesLassa virus Josiah / Oryctolagus cuniculus (rabbit) / Lassa virus (strain Mouse/Sierra Leone/Josiah/1976) / Thermotoga maritima (strain ATCC 43589 / DSM 3109 / JCM 10099 / NBRC 100826 / MSB8) (bacteria)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsPerrett HR / Brouwer PJM / Ward AB
Funding support United States, Netherlands, 4 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)1F31Al172358 United States
Netherlands Organisation for Scientific Research (NWO)Rubicon Fellowship Netherlands
Bill & Melinda Gates FoundationINV-004923 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI71438 United States
CitationJournal: Cell Rep / Year: 2024
Title: Defining bottlenecks and opportunities for Lassa virus neutralization by structural profiling of vaccine-induced polyclonal antibody responses.
Authors: Philip J M Brouwer / Hailee R Perrett / Tim Beaumont / Haye Nijhuis / Sabine Kruijer / Judith A Burger / Ilja Bontjer / Wen-Hsin Lee / James A Ferguson / Martin Schauflinger / Helena Müller- ...Authors: Philip J M Brouwer / Hailee R Perrett / Tim Beaumont / Haye Nijhuis / Sabine Kruijer / Judith A Burger / Ilja Bontjer / Wen-Hsin Lee / James A Ferguson / Martin Schauflinger / Helena Müller-Kräuter / Rogier W Sanders / Thomas Strecker / Marit J van Gils / Andrew B Ward /
Abstract: Lassa fever continues to be a major public health burden in West Africa, yet effective therapies or vaccines are lacking. The isolation of protective neutralizing antibodies against the Lassa virus ...Lassa fever continues to be a major public health burden in West Africa, yet effective therapies or vaccines are lacking. The isolation of protective neutralizing antibodies against the Lassa virus glycoprotein complex (GPC) justifies the development of vaccines that can elicit strong neutralizing antibody responses. However, Lassa vaccine candidates have generally been unsuccessful at doing so, and the associated antibody responses to these vaccines remain poorly characterized. Here, we establish an electron microscopy-based epitope mapping workflow that enables high-resolution structural characterization of polyclonal antibodies to the GPC. By applying this method to rabbits vaccinated with a recombinant GPC vaccine and a GPC-derived virus-like particle, we reveal determinants of neutralization that involve epitopes of the GPC-A competition cluster. Furthermore, by identifying undescribed immunogenic off-target epitopes, we expose the challenges that recombinant GPC vaccines face. By enabling detailed polyclonal antibody characterization, our work ushers in a next generation of more rational Lassa vaccine design.
History
DepositionAug 25, 2023-
Header (metadata) releaseSep 11, 2024-
Map releaseSep 11, 2024-
UpdateNov 20, 2024-
Current statusNov 20, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_41715.png

Downloads & links

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Map

FileDownload / File: emd_41715.map.gz / Format: CCP4 / Size: 476.8 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

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Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.73 Å/pix.
x 500 pix.
= 362.5 Å		0.73 Å/pix.
x 500 pix.
= 362.5 Å		0.73 Å/pix.
x 500 pix.
= 362.5 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.725 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0624
Minimum - Maximum-0.19517925 - 0.39420086
Average (Standard dev.)-0.000057452467 (±0.008455541)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions500500500
Spacing500500500
CellA=B=C: 362.5 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_41715_msk_1.map
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Additional map: #1

Fileemd_41715_additional_1.map
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Half map: #2

Fileemd_41715_half_map_1.map
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Half map: #1

Fileemd_41715_half_map_2.map
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Sample components

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Entire : Heterotrimeric Lassa GPC bound to heterodimeric rabbit polyclonal...

EntireName: Heterotrimeric Lassa GPC bound to heterodimeric rabbit polyclonal fusion-peptide-targeting antibody FP-1
Components
  • Complex: Heterotrimeric Lassa GPC bound to heterodimeric rabbit polyclonal fusion-peptide-targeting antibody FP-1
    • Complex: Glycoprotein G1, Glycoprotein G2, 2-dehydro-3-deoxyphosphogluconate aldolase/4-hydroxy-2-oxoglutarate aldolase fusion protein
      • Protein or peptide: Glycoprotein GP1
      • Protein or peptide: Glycoprotein GP2
    • Complex: Polyclonal antibody FP-1 heavy chain, Polyclonal antibody FP-1 light chain
      • Protein or peptide: Polyclonal Fv heavy chain
      • Protein or peptide: Polyclonal Fv light chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Heterotrimeric Lassa GPC bound to heterodimeric rabbit polyclonal...

SupramoleculeName: Heterotrimeric Lassa GPC bound to heterodimeric rabbit polyclonal fusion-peptide-targeting antibody FP-1
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4

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Supramolecule #2: Glycoprotein G1, Glycoprotein G2, 2-dehydro-3-deoxyphosphoglucona...

SupramoleculeName: Glycoprotein G1, Glycoprotein G2, 2-dehydro-3-deoxyphosphogluconate aldolase/4-hydroxy-2-oxoglutarate aldolase fusion protein
type: complex / ID: 2 / Parent: 1 / Macromolecule list: #3-#4
Source (natural)Organism: Lassa virus Josiah

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Supramolecule #3: Polyclonal antibody FP-1 heavy chain, Polyclonal antibody FP-1 li...

SupramoleculeName: Polyclonal antibody FP-1 heavy chain, Polyclonal antibody FP-1 light chain
type: complex / ID: 3 / Parent: 1 / Macromolecule list: #1-#2
Source (natural)Organism: Oryctolagus cuniculus (rabbit)

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Macromolecule #1: Polyclonal Fv heavy chain

MacromoleculeName: Polyclonal Fv heavy chain / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Oryctolagus cuniculus (rabbit)
Molecular weightTheoretical: 9.890183 KDa
SequenceString: (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK) ...String:
(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK) (UNK)(UNK)(UNK)

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Macromolecule #2: Polyclonal Fv light chain

MacromoleculeName: Polyclonal Fv light chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Oryctolagus cuniculus (rabbit)
Molecular weightTheoretical: 8.698714 KDa
SequenceString: (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK) ...String:
(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)

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Macromolecule #3: Glycoprotein GP1

MacromoleculeName: Glycoprotein GP1 / type: protein_or_peptide / ID: 3 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Lassa virus (strain Mouse/Sierra Leone/Josiah/1976)
Strain: Mouse/Sierra Leone/Josiah/1976
Molecular weightTheoretical: 29.010352 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGQIVTFFQE VPHVIEEVMN IVLIALSVLA VLKGLYNFAT CGLVGLVTFL LLCGRSCTTS LYKGVYELQT LELNMETLNM TMPLSCTKN NSHHYIMVGN ETGLELTLTN TSIINHKFCN LSDAHKKNLY DHALMSIIST FHLSIPNFNQ YEAMSCDFNG G KISVQYNL ...String:
MGQIVTFFQE VPHVIEEVMN IVLIALSVLA VLKGLYNFAT CGLVGLVTFL LLCGRSCTTS LYKGVYELQT LELNMETLNM TMPLSCTKN NSHHYIMVGN ETGLELTLTN TSIINHKFCN LSDAHKKNLY DHALMSIIST FHLSIPNFNQ YEAMSCDFNG G KISVQYNL SHSYAGDAAN HCGTVANGVL QTFMRMAWGG SYIALDSGCG NWDCIMTSYQ YLIIQNTTWE DHCQFSRPSP IG YLGLLSQ RTRDIYISRR LL

UniProtKB: Pre-glycoprotein polyprotein GP complex

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Macromolecule #4: Glycoprotein GP2

MacromoleculeName: Glycoprotein GP2 / type: protein_or_peptide / ID: 4 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Thermotoga maritima (strain ATCC 43589 / DSM 3109 / JCM 10099 / NBRC 100826 / MSB8) (bacteria)
Strain: ATCC 43589 / DSM 3109 / JCM 10099 / NBRC 100826 / MSB8
Molecular weightTheoretical: 44.765047 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: GTFTWTLSDS EGKDTPGGYC LTRWMLIEAE LKCFGNTAVA KCNEKHDEEF CDMLRLFDFN KQAIQRLKAP AQMSIQLINK AVNALINDQ LIMKNHLRDI MCIPYCNYSK YWYLNHTTTG RTSLPKCWLV SNGSYLNETH FSDDIEQQAD NMITEMLQKE Y MERQGGSG ...String:
GTFTWTLSDS EGKDTPGGYC LTRWMLIEAE LKCFGNTAVA KCNEKHDEEF CDMLRLFDFN KQAIQRLKAP AQMSIQLINK AVNALINDQ LIMKNHLRDI MCIPYCNYSK YWYLNHTTTG RTSLPKCWLV SNGSYLNETH FSDDIEQQAD NMITEMLQKE Y MERQGGSG GSGGSGGSGG SEKAAKAEEA ARKMEELFKK HKIVAVLRAN SVEEAIEKAV AVFAGGVHLI EITFTVPDAD TV IKALSVL KEKGAIIGAG TVTSVEQCRK AVESGAEFIV SPHLDEEISQ FCKEKGVFYM PGVMTPTELV KAMKLGHDIL KLF PGEVVG PEFVKAMKGP FPNVKFVPTG GVDLDNVCEW FDAGVLAVGV GDALVEGDPD EVREKAKEFV EKIRGCTEGS LEWS HPQFE K

UniProtKB: Pre-glycoprotein polyprotein GP complex, 2-dehydro-3-deoxyphosphogluconate aldolase/4-hydroxy-2-oxoglutarate aldolase

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Macromolecule #10: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 10 / Number of copies: 14 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

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

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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

Concentration0.1 mg/mL
BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS GLACIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 43.3 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm
Sample stageSpecimen holder model: OTHER / Cooling holder cryogen: NITROGEN

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Image processing

Startup modelType of model: INSILICO MODEL / In silico model: ab initio
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 59236
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
FSC plot (resolution estimation)

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