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- EMDB-49059: L9-targeting immunogen bound to three copies of L9 Fab -

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Basic information

Entry
Database: EMDB / ID: EMD-49059
TitleL9-targeting immunogen bound to three copies of L9 Fab
Map data
Sample
  • Complex: De novo immunogen bound to three copies of L9 Fab
    • Protein or peptide: L9 Fab heavy chain
    • Protein or peptide: L9 Fab light chain
    • Protein or peptide: L9-targeting immunogen
KeywordsImmunogen / Malaria / DE NOVO PROTEIN / IMMUNE SYSTEM-DE NOVO PROTEIN complex
Biological speciesHomo sapiens (human) / Plasmodium falciparum (malaria parasite P. falciparum)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsGarfinkle SE / Lin ZJ / Pallesen J
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Proc Natl Acad Sci U S A / Year: 2025
Title: Machine learning enables de novo multiepitope design of circumsporozoite protein to target trimeric L9 antibody.
Authors: J Andrew D Nelson / Samuel E Garfinkle / Zi Jie Lin / Joyce Park / Amber J Kim / Kelly Bayruns / Madison E McCanna / Kylie M Konrath / Colby J Agostino / Daniel W Kulp / Audrey R Odom John / Jesper Pallesen /
Abstract: Currently approved vaccines for the prevention of malaria provide only partial protection against disease due to high variability in the quality of induced antibodies. These vaccines present the ...Currently approved vaccines for the prevention of malaria provide only partial protection against disease due to high variability in the quality of induced antibodies. These vaccines present the unstructured central repeat region, as well as the C-terminal domain, of the circumsporozoite protein (CSP) of the malaria parasite, [K. L. Williams ., ,1-13 (2024)]. A recently discovered protective monoclonal antibody, L9, recognizes three structured copies of the CSP minor repeat. Similarly to other highly potent antimalarial antibodies, L9 relies on critical homotypic interactions between antibodies for its high protective efficacy [P. Tripathi , , 480-491.e4 (2023); G. M. Martin , ,2815 (2023)]. Here, we report the design of antigens scaffolding one copy of CSP's minor repeat capable of binding L9. To design antigens capable of presenting multiple, structure-based epitopes in one scaffold, we developed a machine learning- driven structural antigen design pipeline, MESODID, tailored to focus on multiepitope vaccine targets. We use this pipeline to design multiple scaffolds that present three copies of the CSP minor repeat. A 3.6 Å cryo-EM structure of our top design, minor repeat targeting immunogen (M-TIM), demonstrates that M-TIM successfully orients three copies of L9, effectively recapitulating its critical homotypic interactions. The wide prevalence of repeated epitopes in key vaccine targets, such as HIV-1 Envelope, SARS-CoV-2 spike, and Influenza Hemagglutinin, suggests that MESODID will have broad utility in creating antigens that incorporate such epitopes, offering a powerful approach to developing vaccines against a range of challenging infections, including malaria.
History
DepositionFeb 5, 2025-
Header (metadata) releaseDec 10, 2025-
Map releaseDec 10, 2025-
UpdateDec 17, 2025-
Current statusDec 17, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_49059.png

Downloads & links

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Map

FileDownload / File: emd_49059.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.95 Å/pix.
x 320 pix.
= 303.2 Å		0.95 Å/pix.
x 320 pix.
= 303.2 Å		0.95 Å/pix.
x 320 pix.
= 303.2 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.9475 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.12
Minimum - Maximum-1.2736264 - 2.0133643
Average (Standard dev.)0.00007361625 (±0.02453469)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 303.2 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: #2

Fileemd_49059_additional_1.map
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Additional map: #1

Fileemd_49059_additional_2.map
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Half map: #2

Fileemd_49059_half_map_1.map
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Half map: #1

Fileemd_49059_half_map_2.map
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Sample components

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Entire : De novo immunogen bound to three copies of L9 Fab

EntireName: De novo immunogen bound to three copies of L9 Fab
Components
  • Complex: De novo immunogen bound to three copies of L9 Fab
    • Protein or peptide: L9 Fab heavy chain
    • Protein or peptide: L9 Fab light chain
    • Protein or peptide: L9-targeting immunogen

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Supramolecule #1: De novo immunogen bound to three copies of L9 Fab

SupramoleculeName: De novo immunogen bound to three copies of L9 Fab / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Molecular weightTheoretical: 170 KDa

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Macromolecule #1: L9 Fab heavy chain

MacromoleculeName: L9 Fab heavy chain / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.475436 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QVKLVESGGG VVQPGRSLRL SCEASGFIFS TYGMHWVRQA PGKGLEWVAV IWFDGSNIYY ADSVKGRFTI SRDNSKNTVF MQMDSLRAE DTAVYYCHRN FYDGSGPFDY WGQGTLVTVS SASTKGPSVF PLAPSSKSTS GGTAALGCLV KDYFPEPVTV S WNSGALTS ...String:
QVKLVESGGG VVQPGRSLRL SCEASGFIFS TYGMHWVRQA PGKGLEWVAV IWFDGSNIYY ADSVKGRFTI SRDNSKNTVF MQMDSLRAE DTAVYYCHRN FYDGSGPFDY WGQGTLVTVS SASTKGPSVF PLAPSSKSTS GGTAALGCLV KDYFPEPVTV S WNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGT QTYICNVNHK PSNTKVDKKV EPKSCDKTH

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Macromolecule #2: L9 Fab light chain

MacromoleculeName: L9 Fab light chain / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.597254 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DIQMTQSPST LSASVGDRVT ITCRASQFIS RWLAWYQQKP GKAPKLLIYK ASSLESGVPS RFSGSGSETH FTLTISSLQP DDVATYYCQ EYTSYGRTFG QGTKVEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS ...String:
DIQMTQSPST LSASVGDRVT ITCRASQFIS RWLAWYQQKP GKAPKLLIYK ASSLESGVPS RFSGSGSETH FTLTISSLQP DDVATYYCQ EYTSYGRTFG QGTKVEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS KDSTYSLSST LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC

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Macromolecule #3: L9-targeting immunogen

MacromoleculeName: L9-targeting immunogen / type: protein_or_peptide / ID: 3
Details: The majority of the backbone and sequence was designed de-novo, but small fragments of the P. falciparum protein CSP are included.
Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Plasmodium falciparum (malaria parasite P. falciparum)
Molecular weightTheoretical: 20.610611 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
MVEIEKKKFS VEEENNKVTL TLCKEKTDGT VTCLTVEWEY EVNPNVDPND QKAFKEITIL SLKEMLGKNF EEFVKLNGKK LKVSIKATI TSNPNVDNEV RLKVKSEDGK IFELCDMYRC DPDEPCIKTP RKCNPNVDLE TIAKRTGSRV VEEEFTMNLK V EKKKEEIE LEGGHHHHHH

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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

Concentration0.03 mg/mL
BufferpH: 7
GridMaterial: GOLD
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV
DetailsGraphene oxide grids, particles concentrated near graphene oxide

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Electron microscopy

MicroscopeTFS GLACIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.5 µm

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Image processing

Particle selectionNumber selected: 5667474
CTF correctionSoftware - Name: cryoSPARC (ver. 4.3.1) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL
In silico model: Superposition of immunogen model from AlphaFold2 with prior structure of trimeric L9 Fab from PDB 8EK1
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.3.1) / Number images used: 434079
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.3.1)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.3.1)
FSC plot (resolution estimation)

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