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- EMDB-26594: Lineage I (Pinneo) Lassa virus glycoprotein bound to 18.5C-M30 Fab -

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Basic information

Entry
Database: EMDB / ID: EMD-26594
TitleLineage I (Pinneo) Lassa virus glycoprotein bound to 18.5C-M30 Fab
Map dataSharpened map
Sample
  • Complex: Lineage I (Pinneo) Lassa virus glycoprotein bound to 18.5C-M30 Fab
    • Protein or peptide: Glycoprotein G1
    • Protein or peptide: 18.5C-M30 Fab Light Chain
    • Protein or peptide: 18.5C-M30 Fab Heavy Chain
    • Protein or peptide: Glycoprotein G2
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Keywordsglycoprotein / antibody / lassa virus / VIRAL PROTEIN / VIRAL PROTEIN-IMMUNE SYSTEM complex
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 speciesLassa mammarenavirus / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.59 Å
AuthorsBuck TK / Enriquez AS / Hastie KM
Funding support United States, 3 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R21 AI137809 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)U19 AI142790 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI141251 United States
CitationJournal: mBio / Year: 2022
Title: Neutralizing Antibodies against Lassa Virus Lineage I.
Authors: Tierra K Buck / Adrian S Enriquez / Sharon L Schendel / Michelle A Zandonatti / Stephanie S Harkins / Haoyang Li / Alex Moon-Walker / James E Robinson / Luis M Branco / Robert F Garry / ...Authors: Tierra K Buck / Adrian S Enriquez / Sharon L Schendel / Michelle A Zandonatti / Stephanie S Harkins / Haoyang Li / Alex Moon-Walker / James E Robinson / Luis M Branco / Robert F Garry / Erica Ollmann Saphire / Kathryn M Hastie /
Abstract: Lassa virus (LASV) is the causative agent of the deadly Lassa fever (LF). Seven distinct LASV lineages circulate through western Africa, among which lineage I (LI), the first to be identified, is ...Lassa virus (LASV) is the causative agent of the deadly Lassa fever (LF). Seven distinct LASV lineages circulate through western Africa, among which lineage I (LI), the first to be identified, is particularly resistant to antibody neutralization. Lineage I LASV evades neutralization by half of known antibodies in the GPC-A antibody competition group and all but one of the antibodies in the GPC-B competition group. Here, we solve two cryo-electron microscopy (cryo-EM) structures of LI GP in complex with a GPC-A and a GPC-B antibody. We used complementary structural and biochemical techniques to identify single-amino-acid substitutions in LI that are responsible for immune evasion by each antibody group. Further, we show that LI infection is more dependent on the endosomal receptor lysosome-associated membrane protein 1 (LAMP1) for viral entry relative to LIV. In the absence of LAMP1, LI requires a more acidic fusion pH to initiate membrane fusion with the host cell relative to LIV. No vaccine or therapeutics are approved to prevent LASV infection or treat LF. All vaccine platforms currently under development present only the LIV GP sequence. However, our data suggest that the high genetic diversity of LASV may be problematic for designing both a broadly reactive immunogen and therapeutic. Here, we examine antibodies that are highly potent against LIV yet are ineffective against LI. By pinpointing LI mutations responsible for this decrease in antibody efficacy, we suggest that future vaccine platforms may need to incorporate specific LI-like mutations in order to generate a broadly neutralizing antibody response against all LASV lineages.
History
DepositionApr 4, 2022-
Header (metadata) releaseJun 15, 2022-
Map releaseJun 15, 2022-
UpdateNov 13, 2024-
Current statusNov 13, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_26594.png

Downloads & links

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Map

FileDownload / File: emd_26594.map.gz / Format: CCP4 / Size: 274.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharpened map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.3 Å/pix.
x 416 pix.
= 539.136 Å		1.3 Å/pix.
x 416 pix.
= 539.136 Å		1.3 Å/pix.
x 416 pix.
= 539.136 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.296 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.001686238 - 2.2448566
Average (Standard dev.)0.00025324424 (±0.011390169)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions416416416
Spacing416416416
CellA=B=C: 539.136 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: Unsharpened map

Fileemd_26594_additional_1.map
AnnotationUnsharpened map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Half map: Half map A

Fileemd_26594_half_map_1.map
AnnotationHalf map A
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_26594_half_map_2.map
Projections & Slices
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Sample components

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Entire : Lineage I (Pinneo) Lassa virus glycoprotein bound to 18.5C-M30 Fab

EntireName: Lineage I (Pinneo) Lassa virus glycoprotein bound to 18.5C-M30 Fab
Components
  • Complex: Lineage I (Pinneo) Lassa virus glycoprotein bound to 18.5C-M30 Fab
    • Protein or peptide: Glycoprotein G1
    • Protein or peptide: 18.5C-M30 Fab Light Chain
    • Protein or peptide: 18.5C-M30 Fab Heavy Chain
    • Protein or peptide: Glycoprotein G2
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Lineage I (Pinneo) Lassa virus glycoprotein bound to 18.5C-M30 Fab

SupramoleculeName: Lineage I (Pinneo) Lassa virus glycoprotein bound to 18.5C-M30 Fab
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Molecular weightTheoretical: 350 KDa

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Macromolecule #1: Glycoprotein G1

MacromoleculeName: Glycoprotein G1 / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Lassa mammarenavirus
Molecular weightTheoretical: 28.987398 KDa
Recombinant expressionOrganism: Drosophila melanogaster (fruit fly)
SequenceString: MGQIITFFQE VPHVIEEVMN IVLIALSLLA ILKGLYNIAT CGIIGLVAFL FLCGKSCSLT LKGGYELQTL ELNMETLNMT MPLSCTKNS SHHYIRVGNE TGLELTLTNT SIINHKFCNL SDAHKKNLYD HALMSIISTF HLSIPNFNQY EAMSCDFNGG K ISVQYNLS ...String:
MGQIITFFQE VPHVIEEVMN IVLIALSLLA ILKGLYNIAT CGIIGLVAFL FLCGKSCSLT LKGGYELQTL ELNMETLNMT MPLSCTKNS SHHYIRVGNE TGLELTLTNT SIINHKFCNL SDAHKKNLYD HALMSIISTF HLSIPNFNQY EAMSCDFNGG K ISVQYNLS HSYAGDAAEH CGTVANGVLQ TFMRMAWGGR YIALDSGCGN WDCIMTSYQY LIIQNTTWED HCQFSRPSPI GY LGLLSQR TRDIYISRRR R

UniProtKB: Pre-glycoprotein polyprotein GP complex

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Macromolecule #2: 18.5C-M30 Fab Light Chain

MacromoleculeName: 18.5C-M30 Fab Light Chain / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 25.880822 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: METDTLLLWV LLLWVPGSTG DDIVLTQSPG TLSLSPGERA TLSCRASQSV ISYYVAWYQH KGGQAPRLLI YGASSRATGV PDRFSGSGS GTDFTLTISS LEPEDFALYY CQYYGSSPLW AFGQGTKVEI KRTVAAPSVF IFPPSDEQLK SGTASVVCLL N NFYPREAK ...String:
METDTLLLWV LLLWVPGSTG DDIVLTQSPG TLSLSPGERA TLSCRASQSV ISYYVAWYQH KGGQAPRLLI YGASSRATGV PDRFSGSGS GTDFTLTISS LEPEDFALYY CQYYGSSPLW AFGQGTKVEI KRTVAAPSVF IFPPSDEQLK SGTASVVCLL N NFYPREAK VQWKVDNALQ SGNSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE VTHQGLSSPV TKSFNRGEC

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Macromolecule #3: 18.5C-M30 Fab Heavy Chain

MacromoleculeName: 18.5C-M30 Fab Heavy Chain / type: protein_or_peptide / ID: 3 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 26.737285 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: METDTLLLWV LLLWVPGSTG DEVQLVQSGG GLVRPGGSLR LSCAAAGFTF KSYSMNWVRQ APGRGLEWVS SITSRGGSKT YYADVVKGR FTVSRDNAKQ SLYLQMNSLR AEDTAIYFCA RSRHSTSQPS YMDVWGRKIT VIVSSASTKG PSVFPLAPSS K STSGGTAA ...String:
METDTLLLWV LLLWVPGSTG DEVQLVQSGG GLVRPGGSLR LSCAAAGFTF KSYSMNWVRQ APGRGLEWVS SITSRGGSKT YYADVVKGR FTVSRDNAKQ SLYLQMNSLR AEDTAIYFCA RSRHSTSQPS YMDVWGRKIT VIVSSASTKG PSVFPLAPSS K STSGGTAA LGCLVKDYFP EPVTVSWNSG ALTSGVHTFP AVLQSSGLYS LSSVVTVPSS SLGTQTYICN VNHKPSNTKV DK RVEPKSC DK

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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 mammarenavirus
Molecular weightTheoretical: 23.348145 KDa
Recombinant expressionOrganism: Drosophila melanogaster (fruit fly)
SequenceString: GTFTWTLSDS EGNETPGGYC LTRWMLIEAE LKCFGNTAVA KCNEKHDEEF CDMLRLFDFN KQAIRRLKAP AQMSIQLINK AVNALINDQ LIMKNHLRDI MCIPYCNYSK YWYLNHTSSG RTSLPKCWLI SNGSYLNETQ FSDDIEQQAD NMITEMLQKE Y LPETGLVD ...String:
GTFTWTLSDS EGNETPGGYC LTRWMLIEAE LKCFGNTAVA KCNEKHDEEF CDMLRLFDFN KQAIRRLKAP AQMSIQLINK AVNALINDQ LIMKNHLRDI MCIPYCNYSK YWYLNHTSSG RTSLPKCWLI SNGSYLNETQ FSDDIEQQAD NMITEMLQKE Y LPETGLVD LEVDDDDKAG WSHPQFEKGG GSGGGSGGGS WSHPQFEK

UniProtKB: Pre-glycoprotein polyprotein GP complex

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Macromolecule #6: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 6 / Number of copies: 22 / 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

BufferpH: 7.5
Component:
ConcentrationFormulaName
50.0 mMC4H11NO3Tris
150.0 mMNaClSodium chloride
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionApplied symmetry - Point group: C3 (3 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.59 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 380210
Initial angle assignmentType: COMMON LINE
Final angle assignmentType: PROJECTION MATCHING
FSC plot (resolution estimation)

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