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- EMDB-26458: Structure of lineage I (Pinneo) Lassa virus glycoprotein bound to... -

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Basic information

Entry
Database: EMDB / ID: EMD-26458
TitleStructure of lineage I (Pinneo) Lassa virus glycoprotein bound to Fab 25.10C
Map dataSharpened map
Sample
  • Complex: Lineage I Lassa virus glycoprotein bound to Fab 25.10C
    • Protein or peptide: 25.10C Fab Heavy Chain
    • Protein or peptide: 25.10C Fab Light Chain
    • Protein or peptide: Glycoprotein G1
    • Protein or peptide: Glycoprotein G2
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Keywordsviral glycoprotein / antibody Fab fragment / 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 / metal ion binding / membrane
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 mammarenavirus
Methodsingle particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsBuck TK / Enriquez AE / 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
DepositionMar 20, 2022-
Header (metadata) releaseJun 15, 2022-
Map releaseJun 15, 2022-
UpdateOct 23, 2024-
Current statusOct 23, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_26458.png

Downloads & links

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Map

FileDownload / File: emd_26458.map.gz / Format: CCP4 / Size: 216 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.)
1.1 Å/pix.
x 384 pix.
= 420.864 Å		1.1 Å/pix.
x 384 pix.
= 420.864 Å		1.1 Å/pix.
x 384 pix.
= 420.864 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.096 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.03
Minimum - Maximum-0.0017336241 - 2.7971716
Average (Standard dev.)0.0005301072 (±0.01708752)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 420.86398 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: Unsharpened map

Fileemd_26458_additional_1.map
AnnotationUnsharpened map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map A

Fileemd_26458_half_map_1.map
AnnotationHalf map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map B

Fileemd_26458_half_map_2.map
AnnotationHalf map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : Lineage I Lassa virus glycoprotein bound to Fab 25.10C

EntireName: Lineage I Lassa virus glycoprotein bound to Fab 25.10C
Components
  • Complex: Lineage I Lassa virus glycoprotein bound to Fab 25.10C
    • Protein or peptide: 25.10C Fab Heavy Chain
    • Protein or peptide: 25.10C Fab Light Chain
    • Protein or peptide: Glycoprotein G1
    • Protein or peptide: Glycoprotein G2
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Lineage I Lassa virus glycoprotein bound to Fab 25.10C

SupramoleculeName: Lineage I Lassa virus glycoprotein bound to Fab 25.10C
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Molecular weightTheoretical: 350 KDa

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Macromolecule #1: 25.10C Fab Heavy Chain

MacromoleculeName: 25.10C Fab Heavy Chain / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.27025 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: QVQLQESGGG LVKPGGSLRL SCTASGFNFN KYNMNWVRQA PGKGLEWVSS ISALSTYIYY ADSLKGRFTV SRDNAKNSLF LQMNSLRDD DTAVYYCARE IRRASTWSAD LWGRGTLVTV SSASTKGPSV FPLAPSSKST SGGTAALGCL VKDYFPEPVT V SWNSGALT ...String:
QVQLQESGGG LVKPGGSLRL SCTASGFNFN KYNMNWVRQA PGKGLEWVSS ISALSTYIYY ADSLKGRFTV SRDNAKNSLF LQMNSLRDD DTAVYYCARE IRRASTWSAD LWGRGTLVTV SSASTKGPSV FPLAPSSKST SGGTAALGCL VKDYFPEPVT V SWNSGALT SGVHTFPAVL QSSGLYSLSS VVTVPSSSLG TQTYICNVNH KPSNTKVDKR VEPKSCDK

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Macromolecule #2: 25.10C Fab Light Chain

MacromoleculeName: 25.10C Fab Light Chain / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 22.812377 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: IQMTQSPSSL SASVGDRVII TCRASQSISS SLNWYQQKPG KAPKLLIYAA VNLETGVPSR FSGSGFGTDF TLAISNVQPE DFATYYCQQ SDTRTFGRGT KLDVKRTVAA PSVFIFPPSD EQLKSGTASV VCLLNNFYPR EAKVQWKVDN ALQSGNSQES V TEQDSKDS ...String:
IQMTQSPSSL SASVGDRVII TCRASQSISS SLNWYQQKPG KAPKLLIYAA VNLETGVPSR FSGSGFGTDF TLAISNVQPE DFATYYCQQ SDTRTFGRGT KLDVKRTVAA PSVFIFPPSD EQLKSGTASV VCLLNNFYPR EAKVQWKVDN ALQSGNSQES V TEQDSKDS TYSLSSTLTL SKADYEKHKV YACEVTHQGL SSPVTKSFNR G

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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 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 #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 #8: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 8 / Number of copies: 10 / 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: 7.4
Component:
ConcentrationFormulaName
50.0 mMC4H11NO3Tris
150.0 mMNaClSodium Chloride
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 298 K

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 55.0 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: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 152874
Initial angle assignmentType: COMMON LINE
Final angle assignmentType: PROJECTION MATCHING
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

5vk2


Chain - Source name: PDB / Chain - Initial model type: experimental model
Output model

PDB-7uds:
Structure of lineage I (Pinneo) Lassa virus glycoprotein bound to Fab 25.10C

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