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- EMDB-26655: Native Lassa glycoprotein in complex with neutralizing antibodies... -

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Basic information

Entry
Database: EMDB / ID: EMD-26655
TitleNative Lassa glycoprotein in complex with neutralizing antibodies 12.1F and 37.2D
Map data
Sample
  • Complex: Native Lassa glycoprotein in complex with 12.1F-scFv and 37.2D-scFv
    • Protein or peptide: 12.1F heavy chain (variable domain)
    • Protein or peptide: 12.1F light chain (variable domain)
    • Protein or peptide: Glycoprotein G1
    • Protein or peptide: Glycoprotein G2
    • Protein or peptide: 37.2D light chain (variable domain)
    • Protein or peptide: 37.2D heavy chain (variable domain)
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Function / homology
Function and homology information


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 / membrane / metal ion binding
Similarity search - Function
Arenavirus glycoprotein, zinc binding domain / Arenavirus glycoprotein / Arenavirus glycoprotein
Similarity search - Domain/homology
Pre-glycoprotein polyprotein GP complex
Similarity search - Component
Biological speciesHomo sapiens (human) / Lassa virus
Methodsingle particle reconstruction / cryo EM / Resolution: 2.75 Å
AuthorsLi H / Saphire EO
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID) United States
CitationJournal: Sci Transl Med / Year: 2022
Title: A cocktail of protective antibodies subverts the dense glycan shield of Lassa virus.
Authors: Haoyang Li / Tierra Buck / Michelle Zandonatti / Jieyun Yin / Alex Moon-Walker / Jingru Fang / Anatoliy Koval / Megan L Heinrich / Megan M Rowland / Ruben Diaz Avalos / Sharon L Schendel / ...Authors: Haoyang Li / Tierra Buck / Michelle Zandonatti / Jieyun Yin / Alex Moon-Walker / Jingru Fang / Anatoliy Koval / Megan L Heinrich / Megan M Rowland / Ruben Diaz Avalos / Sharon L Schendel / Diptiben Parekh / Dawid Zyla / Adrian Enriquez / Stephanie Harkins / Brian Sullivan / Victoria Smith / Onyeka Chukwudozie / Reika Watanabe / James E Robinson / Robert F Garry / Luis M Branco / Kathryn M Hastie / Erica Ollmann Saphire /
Abstract: Developing potent therapeutics and effective vaccines are the ultimate goals in controlling infectious diseases. Lassa virus (LASV), the causative pathogen of Lassa fever (LF), infects hundreds of ...Developing potent therapeutics and effective vaccines are the ultimate goals in controlling infectious diseases. Lassa virus (LASV), the causative pathogen of Lassa fever (LF), infects hundreds of thousands annually, but effective antivirals or vaccines against LASV infection are still lacking. Furthermore, neutralizing antibodies against LASV are rare. Here, we describe biochemical analyses and high-resolution cryo-electron microscopy structures of a therapeutic cocktail of three broadly protective antibodies that target the LASV glycoprotein complex (GPC), previously identified from survivors of multiple LASV infections. Structural and mechanistic analyses reveal compatible neutralizing epitopes and complementary neutralization mechanisms that offer high potency, broad range, and resistance to escape. These antibodies either circumvent or exploit specific glycans comprising the extensive glycan shield of GPC. Further, they require mammalian glycosylation, native GPC cleavage, and proper GPC trimerization. These findings guided engineering of a next-generation GPC antigen suitable for future neutralizing antibody and vaccine discovery. Together, these results explain protective mechanisms of rare, broad, and potent antibodies and identify a strategy for the rational design of therapeutic modalities against LF and related infectious diseases.
History
DepositionApr 14, 2022-
Header (metadata) releaseNov 2, 2022-
Map releaseNov 2, 2022-
UpdateNov 2, 2022-
Current statusNov 2, 2022Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_26655.png

Downloads & links

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Map

FileDownload / File: emd_26655.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.66 Å
Density
Contour LevelBy AUTHOR: 0.07
Minimum - Maximum-0.19064002 - 0.40874007
Average (Standard dev.)-0.0002132425 (±0.009609017)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 337.92 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_26655_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_26655_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Native Lassa glycoprotein in complex with 12.1F-scFv and 37.2D-scFv

EntireName: Native Lassa glycoprotein in complex with 12.1F-scFv and 37.2D-scFv
Components
  • Complex: Native Lassa glycoprotein in complex with 12.1F-scFv and 37.2D-scFv
    • Protein or peptide: 12.1F heavy chain (variable domain)
    • Protein or peptide: 12.1F light chain (variable domain)
    • Protein or peptide: Glycoprotein G1
    • Protein or peptide: Glycoprotein G2
    • Protein or peptide: 37.2D light chain (variable domain)
    • Protein or peptide: 37.2D heavy chain (variable domain)
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Native Lassa glycoprotein in complex with 12.1F-scFv and 37.2D-scFv

SupramoleculeName: Native Lassa glycoprotein in complex with 12.1F-scFv and 37.2D-scFv
type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: #1-#6

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Macromolecule #1: 12.1F heavy chain (variable domain)

MacromoleculeName: 12.1F heavy chain (variable domain) / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 12.731153 KDa
Recombinant expressionOrganism: Drosophila melanogaster (fruit fly)
SequenceString:
QVQLQESGAG LLKPSETLSL SCTVDGESFN GFFWTWIRQP PGKGLEWIGE INHLASTGYN PSLKSRVTIS VDTSKNQFSL KLTSVTAAD TAVYYCARGY SYGFAWPNYH YLDVW

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Macromolecule #2: 12.1F light chain (variable domain)

MacromoleculeName: 12.1F light chain (variable domain) / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 11.602884 KDa
Recombinant expressionOrganism: Drosophila melanogaster (fruit fly)
SequenceString:
EIVLTQSPAT LSLSPGERAT LSCRASQSVS SYLAWYQHKP GQAPRLLIYG ASKRATGIPS RFSGSGSGTD FSLTISSLEP EDFAVYYCQ HRSDWRTTFG QGTRLEI

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Macromolecule #3: Glycoprotein G1

MacromoleculeName: Glycoprotein G1 / type: protein_or_peptide / ID: 3 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Lassa virus / Strain: Mouse/Sierra Leone/Josiah/1976
Molecular weightTheoretical: 29.064402 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 SYIALDSGRG NWDCIMTSYQ YLIIQNTTWE DHCQFSRPSP IG YLGLLSQ RTRDIYISRR LL

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Macromolecule #4: Glycoprotein G2

MacromoleculeName: Glycoprotein G2 / type: protein_or_peptide / ID: 4 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Lassa virus / Strain: Mouse/Sierra Leone/Josiah/1976
Molecular weightTheoretical: 26.797973 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: GTFTWTLSDS EGKDTPGGYC LTRWMLIEAE LKCFGNTAVA KCNEKHDEEF CDMLRLFDFN KQAIQRLKAE AQTSIQLINK AVNALINDQ LIMKNHLRDI MGIPYCNYSK YWYLNHTTTG RTSLPKCWLV SNGSYLNETH FSDDIEQQAD NMITEMLQKE Y MERQGKTP ...String:
GTFTWTLSDS EGKDTPGGYC LTRWMLIEAE LKCFGNTAVA KCNEKHDEEF CDMLRLFDFN KQAIQRLKAE AQTSIQLINK AVNALINDQ LIMKNHLRDI MGIPYCNYSK YWYLNHTTTG RTSLPKCWLV SNGSYLNETH FSDDIEQQAD NMITEMLQKE Y MERQGKTP LGLVDLFVFS TSFYLISIFL HLVKIPTHRH IVGKSCPKPH RLNHMGICSC GLYKQPGVPV KWKR

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Macromolecule #5: 37.2D light chain (variable domain)

MacromoleculeName: 37.2D light chain (variable domain) / type: protein_or_peptide / ID: 5 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 11.412506 KDa
Recombinant expressionOrganism: Drosophila melanogaster (fruit fly)
SequenceString:
ETTLTQSPAT LSVSPGETAT LSCRASQNVI NNLAWYQQKP GQAPRLLIYG ASTRATGIPA RFSGSGSGTE FTLTISSMQS EDFAVYYCQ QYNDWPRSFG QGTRLD

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Macromolecule #6: 37.2D heavy chain (variable domain)

MacromoleculeName: 37.2D heavy chain (variable domain) / type: protein_or_peptide / ID: 6 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 13.946536 KDa
Recombinant expressionOrganism: Drosophila melanogaster (fruit fly)
SequenceString:
EVQLVQSGAE VKKPGASVKV SCKASGYTFT KYGISWVRQA PGQGLEWMGW ISAFNGYTRY GQRFQGKVTM TTDTSTNTAS LEVRTLTSN DTAVYYCARQ YPDQYSSSGW PRLFAMDVWG QGTTVTV

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Macromolecule #13: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 13 / Number of copies: 1 / 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

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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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: 2.0 µm / Nominal defocus min: 1.0 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.75 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 286170

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