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- PDB-9n8j: Stabilized tandem antigen chimera of Pfs230 and Pfs48/45 bound by... -

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Basic information

Entry
Database: PDB / ID: 9n8j
TitleStabilized tandem antigen chimera of Pfs230 and Pfs48/45 bound by potent mAbs
Components
  • (LMIV230-01 Fab ...) x 2
  • Gametocyte surface protein P230,Gametocyte surface protein P45/48
  • RUPA-44 Fab Heavy chain
  • RUPA-44 Fab Kappa chain
  • RUPA-97 Fab Heavy chain
  • RUPA-97 Fab Kappa chain
  • TB31F Fab Heavy chain
  • TB31F Fab Lambda chain
KeywordsIMMUNE SYSTEM / Pfs230 / Pfs48/45 / structure-based immunogen design / human transmission-blocking antibodies / Malaria
Function / homology
Function and homology information


side of membrane / cell surface / plasma membrane
Similarity search - Function
: / 6-Cysteine (6-Cys) domain / 6-Cysteine (6-Cys) domain superfamily / Sexual stage antigen s48/45 domain / 6-Cysteine (6-Cys) domain profile. / Sexual stage antigen s48/45 domain
Similarity search - Domain/homology
Gametocyte surface protein P230 / Gametocyte surface protein P45/48
Similarity search - Component
Biological speciesHomo sapiens (human)
Rattus (rats)
Plasmodium falciparum (malaria parasite P. falciparum)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.22 Å
AuthorsHailemariam, S. / Ivanochko, D. / Julien, J.P.
Funding support United States, Canada, 3items
OrganizationGrant numberCountry
Bill & Melinda Gates Foundation-Gates Foundation (INV-008866 and OPP1156262) -National Institutes of Health grant (1R01AI148557-01A1) -Canadian Institutes for Health Research grant (428410) United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)1R01AI148557-01A1 United States
Canadian Institutes of Health Research (CIHR)428410 Canada
CitationJournal: Nat Commun / Year: 2026
Title: A stabilized tandem antigen chimera that elicits potent malaria transmission-reducing activity.
Authors: Danton Ivanochko / Kazutoyo Miura / Sophia Hailemariam / Rashmi Ravichandran / Yiting Song / Wei-Chiao Huang / Rianne Stoter / Karina Teelen / Geert-Jan van Gemert / Elizabeth M Leaf / ...Authors: Danton Ivanochko / Kazutoyo Miura / Sophia Hailemariam / Rashmi Ravichandran / Yiting Song / Wei-Chiao Huang / Rianne Stoter / Karina Teelen / Geert-Jan van Gemert / Elizabeth M Leaf / Sidney Chan / Christine Men / Anthony Semesi / Carol Shiu / Randall S MacGill / Carole A Long / Matthijs M Jore / Neil P King / Jonathan F Lovell / Jean-Philippe Julien /
Abstract: Malaria parasite transmission remains a barrier to elimination since asymptomatic individuals sustain the infectious reservoir. Transmission-blocking vaccine (TBV) candidates targeting Plasmodium ...Malaria parasite transmission remains a barrier to elimination since asymptomatic individuals sustain the infectious reservoir. Transmission-blocking vaccine (TBV) candidates targeting Plasmodium falciparum (Pf) gametocyte surface proteins Pfs230 and Pfs48/45 have shown promise in clinical trials. Several vaccine candidates have been developed for these antigens, yet it is unclear which elicit the most robust and durable transmission-blocking responses. From structure-function relationships of monoclonal antibodies in complex with both antigens, we report the development of a stabilized tandem antigen chimera (STAC), which presents the most potent epitopes from Pfs230 domain 1 (Pfs230-D1) and Pfs48/45 domain 3 (Pfs48/45-D3) in a single construct, while masking non-functional epitopes using an engineered pseudo-native domain disposition. Iterative structure-guided optimization improved antigen yields and stability, while nanoparticle-based multimerization enhanced the functional transmission-reducing activity elicited by the immunogen in female mice. Immunizations with STAC genetically conjugated to self-assembling protein nanoparticles elicited antibodies with potent transmission-reducing activity comparable or superior to the multimerized Pfs230-D1 and Pfs48/45-D3. These findings establish STAC as a promising next-generation TBV candidate to disrupt malaria transmission and accelerate elimination efforts. More broadly, our results support the engineering of highly ordered and stable multi-domain antigens in a single protein as a strategy for the cost-efficient development of multi-component vaccines.
History
DepositionFeb 8, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 4, 2026Provider: repository / Type: Initial release
Revision 1.0Feb 4, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Feb 4, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Feb 4, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Feb 4, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Feb 4, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Feb 4, 2026Data content type: Mask / Part number: 1 / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0Feb 4, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Jun 10, 2026Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update
Revision 1.1Jun 10, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin
Data content type: EM metadata / EM metadata ...EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: RUPA-97 Fab Heavy chain
C: RUPA-97 Fab Kappa chain
D: RUPA-44 Fab Heavy chain
E: RUPA-44 Fab Kappa chain
F: TB31F Fab Heavy chain
G: TB31F Fab Lambda chain
H: LMIV230-01 Fab Heavy chain
I: LMIV230-01 Fab Kappa chain
X: Gametocyte surface protein P230,Gametocyte surface protein P45/48
hetero molecules


Theoretical massNumber of molelcules
Total (without water)226,75210
Polymers226,3849
Non-polymers3671
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Antibody , 8 types, 8 molecules BCDEFGHI

#1: Antibody RUPA-97 Fab Heavy chain


Mass: 24074.934 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293F / Production host: Homo sapiens (human)
#2: Antibody RUPA-97 Fab Kappa chain


Mass: 23511.209 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293F / Production host: Homo sapiens (human)
#3: Antibody RUPA-44 Fab Heavy chain


Mass: 24277.332 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293F / Production host: Homo sapiens (human)
#4: Antibody RUPA-44 Fab Kappa chain


Mass: 23483.105 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293F / Production host: Homo sapiens (human)
#5: Antibody TB31F Fab Heavy chain


Mass: 23841.736 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus (rats) / Cell line (production host): HEK293F / Production host: Homo sapiens (human)
#6: Antibody TB31F Fab Lambda chain


Mass: 23256.627 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus (rats) / Cell line (production host): HEK293F / Production host: Homo sapiens (human)
#7: Antibody LMIV230-01 Fab Heavy chain


Mass: 23340.297 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293 F / Production host: Homo sapiens (human)
#8: Antibody LMIV230-01 Fab Kappa chain


Mass: 23754.551 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293F / Production host: Homo sapiens (human)

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Protein / Sugars , 2 types, 2 molecules X

#10: Polysaccharide alpha-L-fucopyranose-(1-6)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 367.349 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
LFucpa1-6DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/2,2,1/[a2122h-1b_1-5_2*NCC/3=O][a1221m-1a_1-5]/1-2/a6-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(6+1)][a-L-Fucp]{}}LINUCSPDB-CARE
#9: Protein Gametocyte surface protein P230,Gametocyte surface protein P45/48


Mass: 36844.469 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum (malaria parasite P. falciparum)
Gene: PFS230, PF230, S230, PF3D7_0209000, PF45/48, PFS45-48, PFS45/48, PF13_0247, PF3D7_1346700
Cell line (production host): HEK293F / Production host: Homo sapiens (human) / References: UniProt: P68874, UniProt: Q8I6T1

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Stabilized tandem antigen chimera of Pfs230 and Pfs48/45 bound by four potent mAbs
Type: COMPLEX / Entity ID: #1-#9 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
Buffer component
IDConc.NameFormulaBuffer-ID
1150 mMsodium chlorideNaCl1
220 mMTrisTris-HCl1
30.13 CMCDDMC24H46O111
SpecimenConc.: 5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: Stabilized tandem antigen chimera of Pfs230 and Pfs48/45, complexed with Fabs RUPA-44, TB31F, LMIV1, and RUPA-97.
Specimen supportGrid material: GOLD / Grid type: Homemade
VitrificationInstrument: LEICA EM GP / Cryogen name: ETHANE / Humidity: 90 % / Chamber temperature: 277 K
Details: A Leica Automatic Plunge Freezer EM GP2 was used for sample freezing.

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 130000 X / Nominal defocus max: 2300 nm / Nominal defocus min: 700 nm
Specimen holderSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 52 e/Å2 / Film or detector model: TFS FALCON 4i (4k x 4k)
Details: Images were collected at average electron doses per image of 50 and 53.7 electrons per square Angstrom during two data collections.
EM imaging opticsEnergyfilter name: TFS Selectris X / Energyfilter slit width: 10 eV

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Processing

EM software
IDNameVersionCategory
1cryoSPARCv4.5.2particle selection
2EPUimage acquisition
4cryoSPARCv4.5.2CTF correction
7UCSF ChimeraXmodel fitting
9PHENIXmodel refinement
10Cootmodel refinement
11cryoSPARCv4.5.2initial Euler assignment
12cryoSPARCv4.5.2final Euler assignment
13cryoSPARCv4.5.2classification
14cryoSPARCv4.5.23D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.22 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 147546 / Symmetry type: POINT
Atomic model building
IDPDB-ID 3D fitting-IDAccession codeSource nameType
16.0E+6316.0E+63PDBexperimental model
27UXL

7uxl

17UXLPDBexperimental model
37UVQ

7uvq

17UVQPDBexperimental model
47UFW

7ufw

17UFWPDBexperimental model
RefinementHighest resolution: 3.22 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0049732
ELECTRON MICROSCOPYf_angle_d0.60313207
ELECTRON MICROSCOPYf_dihedral_angle_d10.983561
ELECTRON MICROSCOPYf_chiral_restr0.0441461
ELECTRON MICROSCOPYf_plane_restr0.0041675

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