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- EMDB-41302: Lassa GPC trimer in complex with Fab GP23 -

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Basic information

Entry
Database: EMDB / ID: EMD-41302
TitleLassa GPC trimer in complex with Fab GP23
Map datasharpened map
Sample
  • Complex: Lassa GPC Trimer in complex with Fab GP23
    • Complex: Lassa GPC Trimer
    • Complex: Fab GP23
Keywordsvaccine / GPC / GP1 / GP2 / VIRAL PROTEIN
Biological speciesLassa virus Josiah / Cavia porcellus (domestic guinea pig)
Methodsingle particle reconstruction / cryo EM / Resolution: 5.4 Å
AuthorsGorman J / Kwong PD
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM103310 United States
Simons FoundationSF349247 United States
CitationJournal: Nat Commun / Year: 2024
Title: Cleavage-intermediate Lassa virus trimer elicits neutralizing responses, identifies neutralizing nanobodies, and reveals an apex-situated site-of-vulnerability.
Authors: Jason Gorman / Crystal Sao-Fong Cheung / Zhijian Duan / Li Ou / Maple Wang / Xuejun Chen / Cheng Cheng / Andrea Biju / Yaping Sun / Pengfei Wang / Yongping Yang / Baoshan Zhang / Jeffrey C ...Authors: Jason Gorman / Crystal Sao-Fong Cheung / Zhijian Duan / Li Ou / Maple Wang / Xuejun Chen / Cheng Cheng / Andrea Biju / Yaping Sun / Pengfei Wang / Yongping Yang / Baoshan Zhang / Jeffrey C Boyington / Tatsiana Bylund / Sam Charaf / Steven J Chen / Haijuan Du / Amy R Henry / Tracy Liu / Edward K Sarfo / Chaim A Schramm / Chen-Hsiang Shen / Tyler Stephens / I-Ting Teng / John-Paul Todd / Yaroslav Tsybovsky / Raffaello Verardi / Danyi Wang / Shuishu Wang / Zhantong Wang / Cheng-Yan Zheng / Tongqing Zhou / Daniel C Douek / John R Mascola / David D Ho / Mitchell Ho / Peter D Kwong /
Abstract: Lassa virus (LASV) infection is expanding outside its traditionally endemic areas in West Africa, posing a pandemic biothreat. LASV-neutralizing antibodies, moreover, have proven difficult to elicit. ...Lassa virus (LASV) infection is expanding outside its traditionally endemic areas in West Africa, posing a pandemic biothreat. LASV-neutralizing antibodies, moreover, have proven difficult to elicit. To gain insight into LASV neutralization, here we develop a prefusion-stabilized LASV glycoprotein trimer (GPC), pan it against phage libraries comprising single-domain antibodies (nanobodies) from shark and camel, and identify one, D5, which neutralizes LASV. Cryo-EM analyses reveal D5 to recognize a cleavage-dependent site-of-vulnerability at the trimer apex. The recognized site appears specific to GPC intermediates, with protomers lacking full cleavage between GP1 and GP2 subunits. Guinea pig immunizations with the prefusion-stabilized cleavage-intermediate LASV GPC, first as trimer and then as a nanoparticle, induce neutralizing responses, targeting multiple epitopes including that of D5; we identify a neutralizing antibody (GP23) from the immunized guinea pigs. Collectively, our findings define a prefusion-stabilized GPC trimer, reveal an apex-situated site-of-vulnerability, and demonstrate elicitation of LASV-neutralizing responses by a cleavage-intermediate LASV trimer.
History
DepositionJul 21, 2023-
Header (metadata) releaseAug 16, 2023-
Map releaseAug 16, 2023-
UpdateFeb 28, 2024-
Current statusFeb 28, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_41302.png

Downloads & links

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Map

FileDownload / File: emd_41302.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationsharpened map
Voxel sizeX=Y=Z: 1.083 Å
Density
Contour LevelBy AUTHOR: 0.13
Minimum - Maximum-0.5879434 - 0.94457024
Average (Standard dev.)0.00014740335 (±0.015126369)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 433.19998 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_41302_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: unsharpened map

Fileemd_41302_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_41302_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_41302_half_map_2.map
Annotationhalf map B
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : Lassa GPC Trimer in complex with Fab GP23

EntireName: Lassa GPC Trimer in complex with Fab GP23
Components
  • Complex: Lassa GPC Trimer in complex with Fab GP23
    • Complex: Lassa GPC Trimer
    • Complex: Fab GP23

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Supramolecule #1: Lassa GPC Trimer in complex with Fab GP23

SupramoleculeName: Lassa GPC Trimer in complex with Fab GP23 / type: complex / ID: 1 / Parent: 0

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Supramolecule #2: Lassa GPC Trimer

SupramoleculeName: Lassa GPC Trimer / type: complex / ID: 2 / Parent: 1
Source (natural)Organism: Lassa virus Josiah

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Supramolecule #3: Fab GP23

SupramoleculeName: Fab GP23 / type: complex / ID: 3 / Parent: 1
Source (natural)Organism: Cavia porcellus (domestic guinea pig)

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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

Concentration2 mg/mL
BufferpH: 7.4 / Details: PBS
VitrificationCryogen name: ETHANE / Chamber humidity: 90 % / Chamber temperature: 293 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.8 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Detector mode: COUNTING / Number grids imaged: 1 / Average exposure time: 2.0 sec. / Average electron dose: 51.37 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Initial angle assignmentType: NOT APPLICABLE
Final 3D classificationSoftware - Name: cryoSPARC (ver. 3)
Final angle assignmentType: NOT APPLICABLE
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 5.4 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 3) / Number images used: 164661

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Atomic model buiding 1

RefinementSpace: REAL

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