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- EMDB-48275: Native tagless Lassa virus spike complex bound to ARN-75039 at pH 8.0 -

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Basic information

Entry
Database: EMDB / ID: EMD-48275
TitleNative tagless Lassa virus spike complex bound to ARN-75039 at pH 8.0
Map dataRaw map
Sample
  • Complex: Spike complex of Lassa virus bound by 12.1F and ARN-75039
    • Protein or peptide: Glycoprotein G2
    • Protein or peptide: Glycoprotein G1
    • Protein or peptide: 12.1F Heavy chain
    • Protein or peptide: 12.1F Light chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: UNKNOWN LIGAND
  • Ligand: (4S)-3-(4-tert-butoxyphenyl)-7-methyl-6-{4-[(propan-2-yl)oxy]phenyl}imidazo[1,2-a]pyridine
  • Ligand: water
KeywordsSpike complex / VIRAL PROTEIN
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 speciesLassa virus Josiah / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.01 Å
AuthorsCohen-Dvashi H / Katz M / Diskin R
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Cell Host Microbe / Year: 2025
Title: pH-induced conformational changes and inhibition of the Lassa virus spike complex.
Authors: Michael Katz / Hadas Cohen-Dvashi / Sarah Borni / John Ruedas / Greg Henkel / Ken McCormack / Ron Diskin /
Abstract: Lassa virus (LASV) is a devastating human pathogen with no vaccines and limited therapeutics. The LASV class-I spike complex engages target cells via binding its primary host receptor, matriglycan, ...Lassa virus (LASV) is a devastating human pathogen with no vaccines and limited therapeutics. The LASV class-I spike complex engages target cells via binding its primary host receptor, matriglycan, followed by macropinocytosis and binding of its secondary receptor, lysosomal-associated membrane protein 1 (LAMP1), to trigger virus fusion. This process occurs across multiple pH-dependent steps, but the molecular events remain largely unknown. Through high-resolution structures, we study the pH-induced conformational changes of the spike preceding membrane fusion. We reveal pH-sensitive metal coordination sites that control the integrity of the spike's native state, elucidate a reorganization of the spike's transmembrane region, and provide a mechanism for dissociation from its primary receptor. Using the entry inhibitor ARN-75039, we validate our findings and establish the molecular basis for the binding and function of this investigational drug. These data define the molecular basis for the cell entry of LASV and will promote efforts in combating this virus and potentially related viral pathogens.
History
DepositionDec 11, 2024-
Header (metadata) releaseAug 27, 2025-
Map releaseAug 27, 2025-
UpdateSep 24, 2025-
Current statusSep 24, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_48275.png

Downloads & links

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Map

FileDownload / File: emd_48275.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationRaw map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.82 Å/pix.
x 360 pix.
= 296.712 Å		0.82 Å/pix.
x 360 pix.
= 296.712 Å		0.82 Å/pix.
x 360 pix.
= 296.712 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.8242 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.04
Minimum - Maximum-0.21260443 - 0.4580315
Average (Standard dev.)0.00009475183 (±0.00767006)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 296.712 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: Local-resolution filtered map

Fileemd_48275_additional_1.map
AnnotationLocal-resolution filtered map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map B

Fileemd_48275_half_map_1.map
AnnotationHalf map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map A

Fileemd_48275_half_map_2.map
AnnotationHalf map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Spike complex of Lassa virus bound by 12.1F and ARN-75039

EntireName: Spike complex of Lassa virus bound by 12.1F and ARN-75039
Components
  • Complex: Spike complex of Lassa virus bound by 12.1F and ARN-75039
    • Protein or peptide: Glycoprotein G2
    • Protein or peptide: Glycoprotein G1
    • Protein or peptide: 12.1F Heavy chain
    • Protein or peptide: 12.1F Light chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: UNKNOWN LIGAND
  • Ligand: (4S)-3-(4-tert-butoxyphenyl)-7-methyl-6-{4-[(propan-2-yl)oxy]phenyl}imidazo[1,2-a]pyridine
  • Ligand: water

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Supramolecule #1: Spike complex of Lassa virus bound by 12.1F and ARN-75039

SupramoleculeName: Spike complex of Lassa virus bound by 12.1F and ARN-75039
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Lassa virus Josiah

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Macromolecule #1: Glycoprotein G2

MacromoleculeName: Glycoprotein G2 / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Lassa virus Josiah
Molecular weightTheoretical: 26.828064 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: GTFTWTLSDS EGKDTPGGYC LTRWMLIEAE LKCFGNTAVA KCNEKHDEEF CDMLRLFDFN KQAIQRLKAE AQMSIQLINK AVNALINDQ LIMKNHLRDI MGIPYCNYSK YWYLNHTTTG RTSLPKCWLV SNGSYLNETH FSDDIEQQAD NMITEMLQKE Y MERQGKTP ...String:
GTFTWTLSDS EGKDTPGGYC LTRWMLIEAE LKCFGNTAVA KCNEKHDEEF CDMLRLFDFN KQAIQRLKAE AQMSIQLINK AVNALINDQ LIMKNHLRDI MGIPYCNYSK YWYLNHTTTG RTSLPKCWLV SNGSYLNETH FSDDIEQQAD NMITEMLQKE Y MERQGKTP LGLVDLFVFS TSFYLISIFL HLVKIPTHRH IVGKSCPKPH RLNHMGICSC GLYKQPGVPV KWKR

UniProtKB: Pre-glycoprotein polyprotein GP complex

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Macromolecule #2: Glycoprotein G1

MacromoleculeName: Glycoprotein G1 / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Lassa virus Josiah
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

UniProtKB: Pre-glycoprotein polyprotein GP complex

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Macromolecule #3: 12.1F Heavy chain

MacromoleculeName: 12.1F Heavy chain / type: protein_or_peptide / ID: 3 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 26.79373 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QVQLQESGAG LLKPSETLSL SCTVDGESFN GFFWTWIRQP PGKGLEWIGE INHLASTGYN PSLKSRVTIS VDTSKNQFSL KLTSVTAAD TAVYYCARGY SYGFAWPNYH YLDVWGKGTT VTVSSASTKG PSVFPLAPSS KSTSGGTAAL GCLVKDYFPE P VTVSWNSG ...String:
QVQLQESGAG LLKPSETLSL SCTVDGESFN GFFWTWIRQP PGKGLEWIGE INHLASTGYN PSLKSRVTIS VDTSKNQFSL KLTSVTAAD TAVYYCARGY SYGFAWPNYH YLDVWGKGTT VTVSSASTKG PSVFPLAPSS KSTSGGTAAL GCLVKDYFPE P VTVSWNSG ALTSGVHTFP AVLQSSGLYS LSSVVTVPSS SLGTQTYICN VNHKPSNTKV DKRVEPKSCD KTHGGDYKDD DD KGTENLY FQ

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Macromolecule #4: 12.1F Light chain

MacromoleculeName: 12.1F Light chain / type: protein_or_peptide / ID: 4 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.492086 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EIVLTQSPAT LSLSPGERAT LSCRASQSVS SYLAWYQHKP GQAPRLLIYG ASKRATGIPS RFSGSGSGTD FSLTISSLEP EDFAVYYCQ HRSDWRTTFG QGTRLEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS ...String:
EIVLTQSPAT LSLSPGERAT LSCRASQSVS SYLAWYQHKP GQAPRLLIYG ASKRATGIPS RFSGSGSGTD FSLTISSLEP EDFAVYYCQ HRSDWRTTFG QGTRLEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS KDSTYSLSST LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC

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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: 10 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

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

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Macromolecule #14: UNKNOWN LIGAND

MacromoleculeName: UNKNOWN LIGAND / type: ligand / ID: 14 / Number of copies: 2 / Formula: UNX
Molecular weightTheoretical: 54.938 Da
Chemical component information


ChemComp, No image

ChemComp-UNL:
Unknown ligand

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Macromolecule #15: (4S)-3-(4-tert-butoxyphenyl)-7-methyl-6-{4-[(propan-2-yl)oxy]phen...

MacromoleculeName: (4S)-3-(4-tert-butoxyphenyl)-7-methyl-6-{4-[(propan-2-yl)oxy]phenyl}imidazo[1,2-a]pyridine
type: ligand / ID: 15 / Number of copies: 1 / Formula: A1BK9
Molecular weightTheoretical: 414.539 Da

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Macromolecule #16: water

MacromoleculeName: water / type: ligand / ID: 16 / Number of copies: 983 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 38.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.6 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL / In silico model: stochastic gradient descent
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.01 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 523003
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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