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- PDB-8u1p: Local refinement of Plasmodium falciparum gametocyte surface prot... -

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Basic information

Entry
Database: PDB / ID: 8u1p
TitleLocal refinement of Plasmodium falciparum gametocyte surface protein Pfs48/45 Domains 1 and 2 in complex with neutralizing antibodies
Components
  • Gametocyte surface protein P45/48
  • RUPA154 Fab Heavy Chain
  • RUPA154 Fab Light Chain
  • RUPA58 Fab Heavy Chain
  • RUPA58 Fab Light Chain
KeywordsCELL INVASION/Immune System / transmission blocking vaccine / antibody / malaria / CELL INVASION / CELL INVASION-Immune System complex
Function / homology6-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 / side of membrane / cell surface / plasma membrane / Gametocyte surface protein P45/48
Function and homology information
Biological speciesPlasmodium falciparum 3D7 (eukaryote)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsKucharska, I. / Hailemariam, S. / Ivanochko, D. / Rubinstein, J. / Julien, J.P.
Funding support Canada, Netherlands, 8items
OrganizationGrant numberCountry
CIFAR Azrieli Global Scholars Canada
Ontario Early Researcher Awards Canada
Canada Research Chairs Canada
Canada Foundation for Innovation Canada
Ontario Research Fund Canada
Canadian Institutes of Health Research (CIHR) Canada
Other governmentCanada Graduate Scholarships Doctoral Award Canada
Netherlands Organisation for Scientific Research (NWO)192.061 Netherlands
CitationJournal: Nat Struct Mol Biol / Year: 2025
Title: Structural elucidation of full-length Pfs48/45 in complex with potent monoclonal antibodies isolated from a naturally exposed individual.
Authors: Iga Kucharska / Danton Ivanochko / Sophia Hailemariam / Maartje R Inklaar / Hee Ryung Kim / Karina Teelen / Rianne Stoter / Marga van de Vegte-Bolmer / Geert-Jan van Gemert / Anthony Semesi ...Authors: Iga Kucharska / Danton Ivanochko / Sophia Hailemariam / Maartje R Inklaar / Hee Ryung Kim / Karina Teelen / Rianne Stoter / Marga van de Vegte-Bolmer / Geert-Jan van Gemert / Anthony Semesi / Brandon McLeod / Ahyoung Ki / Won-Kyu Lee / John L Rubinstein / Matthijs M Jore / Jean-Philippe Julien /
Abstract: Biomedical interventions that block the transmission of Plasmodium falciparum (Pf) from humans to mosquitoes may be critical for malaria elimination. Pfs48/45, a gamete-surface protein essential for ...Biomedical interventions that block the transmission of Plasmodium falciparum (Pf) from humans to mosquitoes may be critical for malaria elimination. Pfs48/45, a gamete-surface protein essential for Pf development in the mosquito midgut, is a target of clinical-stage transmission-blocking vaccines and monoclonal antibodies (mAbs) that disrupt Pf transmission to mosquitoes. Antibodies directed to domain 3 of Pfs48/45 have been structurally and functionally described; however, in-depth information about other inhibitory epitopes on Pfs48/45 is currently limited. Here, we present a cryo-electron microscopy structure of full-length Pfs48/45 in complex with potent human mAbs targeting all three domains. Our data indicate that although Pfs48/45 domains 1 and 2 are rigidly coupled, there is substantial conformational flexibility between domains 2 and 3. Characterization of mAbs against domain 1 revealed the presence of a conformational epitope class that is largely conserved across Pf field isolates and is associated with recognition by potent antibodies. Our study provides insights into epitopes across full-length Pfs48/45 and has implications for the design of next-generation malaria interventions.
History
DepositionSep 1, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 12, 2025Provider: repository / Type: Initial release
Revision 1.0Mar 12, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Mar 12, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 12, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 12, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Mar 12, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Jun 4, 2025Group: 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.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
A: Gametocyte surface protein P45/48
H: RUPA154 Fab Heavy Chain
L: RUPA154 Fab Light Chain
C: RUPA58 Fab Light Chain
B: RUPA58 Fab Heavy Chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)142,2318
Polymers141,1615
Non-polymers1,0703
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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Protein , 1 types, 1 molecules A

#1: Protein Gametocyte surface protein P45/48


Mass: 46250.371 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum 3D7 (eukaryote) / Gene: PF45/48 / Production host: Homo sapiens (human) / References: UniProt: Q8I6T1

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Antibody , 4 types, 4 molecules HLCB

#2: Antibody RUPA154 Fab Heavy Chain


Mass: 24241.197 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#3: Antibody RUPA154 Fab Light Chain


Mass: 22898.381 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#4: Antibody RUPA58 Fab Light Chain


Mass: 23355.043 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#5: Antibody RUPA58 Fab Heavy Chain


Mass: 24416.352 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)

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Sugars , 2 types, 3 molecules

#6: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#7: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Details

Has ligand of interestN
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: complex of Pfs48/45, RUPA58 and RUPA154 / Type: COMPLEX / Entity ID: #2-#5 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Plasmodium falciparum 3D7 (eukaryote)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7
Buffer component
IDConc.NameFormulaBuffer-ID
150 mMTris-buffered saline2-Amino-2-(hydroxymethyl)propane-1,3-diol1
2150 mMSodium chlorideNaCl1
SpecimenConc.: 0.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 400 divisions/in. / Grid type: Homemade
VitrificationInstrument: LEICA EM GP / Cryogen name: ETHANE / Humidity: 90 % / Chamber temperature: 277 K
Details: sample was frozen with Leica Automatic Plunge Freezer EM GP2

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 75000 X / Nominal defocus max: 2000 nm / Nominal defocus min: 500 nm / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 8.83 sec. / Electron dose: 48.69 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) / Num. of real images: 7744

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Processing

EM software
IDNameVersionCategoryDetails
1cryoSPARC4particle selection
2EPU2image acquisition
4cryoSPARC4CTF correction
7UCSF Chimeramodel fitting
11cryoSPARC4classification
12cryoSPARC43D reconstruction
13PHENIX1.19model refinementReal-space refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 6424191
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 306744
Details: Local refinement was performed with a mask including domains D1 and D2 of Pfs48/45 and variable regions of RUPA-58 and RUPA-154 Fabs
Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Atomic model building

3D fitting-ID: 1 / Source name: PDB / Type: experimental model

IDPDB-IDPdb chain-IDAccession codeChain-IDInitial refinement model-ID
17ZXG

7zxg

A7ZXGA1
28U70

8u70

B8U70B
38U70

8u70

C8U70C
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0044975
ELECTRON MICROSCOPYf_angle_d0.8926796
ELECTRON MICROSCOPYf_dihedral_angle_d4.944748
ELECTRON MICROSCOPYf_chiral_restr0.088781
ELECTRON MICROSCOPYf_plane_restr0.007866

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