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- EMDB-41822: Local refinement of Plasmodium falciparum gametocyte surface prot... -

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Entry
Database: EMDB / ID: EMD-41822
TitleLocal refinement of Plasmodium falciparum gametocyte surface protein Pfs48/45 Domains 1 and 2 in complex with neutralizing antibodies
Map dataLocal refinement of Plasmodium falciparum gametocyte surface protein Pfs48/45 Domains 1 and 2 in complex with neutralizing antibodies
Sample
  • Complex: complex of Pfs48/45, RUPA58 and RUPA154
    • Protein or peptide: RUPA154 Fab Heavy Chain
    • Protein or peptide: RUPA154 Fab Light Chain
    • Protein or peptide: RUPA58 Fab Light Chain
    • Protein or peptide: RUPA58 Fab Heavy Chain
  • Protein or peptide: Gametocyte surface protein P45/48
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Keywordstransmission 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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsKucharska I / Hailemariam S / Ivanochko D / Rubinstein J / Julien JP
Funding support Canada, Netherlands, 8 items
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, 2023-
Header (metadata) releaseMar 12, 2025-
Map releaseMar 12, 2025-
UpdateJun 4, 2025-
Current statusJun 4, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_41822.png

Downloads & links

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Map

FileDownload / File: emd_41822.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationLocal refinement of Plasmodium falciparum gametocyte surface protein Pfs48/45 Domains 1 and 2 in complex with neutralizing antibodies
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.03 Å/pix.
x 360 pix.
= 370.8 Å		1.03 Å/pix.
x 360 pix.
= 370.8 Å		1.03 Å/pix.
x 360 pix.
= 370.8 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.03 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 5.0
Minimum - Maximum-0.06591939 - 16.485064999999999
Average (Standard dev.)0.0050837435 (±0.20492706)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 370.8 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half Map B

Fileemd_41822_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_41822_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 : complex of Pfs48/45, RUPA58 and RUPA154

EntireName: complex of Pfs48/45, RUPA58 and RUPA154
Components
  • Complex: complex of Pfs48/45, RUPA58 and RUPA154
    • Protein or peptide: RUPA154 Fab Heavy Chain
    • Protein or peptide: RUPA154 Fab Light Chain
    • Protein or peptide: RUPA58 Fab Light Chain
    • Protein or peptide: RUPA58 Fab Heavy Chain
  • Protein or peptide: Gametocyte surface protein P45/48
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: complex of Pfs48/45, RUPA58 and RUPA154

SupramoleculeName: complex of Pfs48/45, RUPA58 and RUPA154 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #2-#5
Source (natural)Organism: Plasmodium falciparum 3D7 (eukaryote)

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Macromolecule #1: Gametocyte surface protein P45/48

MacromoleculeName: Gametocyte surface protein P45/48 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Plasmodium falciparum 3D7 (eukaryote)
Molecular weightTheoretical: 46.250371 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: NNDFCKPSSL NSEISGFIGY KCNFSNEGVH NLKPDMRERR SIFCTIHSYF IYDKIRLIIP KKSSSPEFKI LPEKCFQKVY TDYENRVET DISELGLIEY EIEENDTNPN YNERTITISP FSPKDIEFFC FCDNTEKVIS SIEGRSAMVH VRVLKYPHNI L FTNLTNDL ...String:
NNDFCKPSSL NSEISGFIGY KCNFSNEGVH NLKPDMRERR SIFCTIHSYF IYDKIRLIIP KKSSSPEFKI LPEKCFQKVY TDYENRVET DISELGLIEY EIEENDTNPN YNERTITISP FSPKDIEFFC FCDNTEKVIS SIEGRSAMVH VRVLKYPHNI L FTNLTNDL FTYLPKTYNE SNFVSNVLEV ELNDGELFVL ACELINKKCF QEGKEKALYK SNKIIYHKNL TIFKAPFYVT SK DVNTECT CKFKNNNYKI VLKPKYEKKV IHGCNFSSNV SSKYTFTDSL DISLVDDSAH ISCNVHLSEP KYNHLVGLNC PGD IIPDCF FQVYQPEREE LEPSNIVYLS SQINIGDIEY YEDAEGDDKI KLFLIVGSVP KTTSFTCICK KDKKSAYMTV TIDS A

UniProtKB: Gametocyte surface protein P45/48

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Macromolecule #2: RUPA154 Fab Heavy Chain

MacromoleculeName: RUPA154 Fab Heavy Chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.241197 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QVQLVQSGAE VRKPGASVKV SCRTSGYTFT DYYMHWVRQA PGEGLEWMGS INPKSGGTSY AERFQGRVTM TMETSVSTAY LDLSSLRSD DTAVYYCARL LYSRAVYYYG MDVWGQGTTV TVSSASTKGP SVFPLAPSSK STSGGTAALG CLVKDYFPEP V TVSWNSGA ...String:
QVQLVQSGAE VRKPGASVKV SCRTSGYTFT DYYMHWVRQA PGEGLEWMGS INPKSGGTSY AERFQGRVTM TMETSVSTAY LDLSSLRSD DTAVYYCARL LYSRAVYYYG MDVWGQGTTV TVSSASTKGP SVFPLAPSSK STSGGTAALG CLVKDYFPEP V TVSWNSGA LTSGVHTFPA VLQSSGLYSL SSVVTVPSSS LGTQTYICNV NHKPSNTKVD KKVEPKSC

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Macromolecule #3: RUPA154 Fab Light Chain

MacromoleculeName: RUPA154 Fab Light Chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 22.898381 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: YELTQPPSVS VAPGKTARIT CGGKDLGSKS VHWYQQKPGQ APVLVIYYDN IRPSGIPERF SGSNSGNTAT LTISRVEAGD EADYYCQVW DSSSDHYVFG RGAKVTVLGQ PKAAPSVTLF PPSSEELQAN KATLVCLISD FYPGAVTVAW KADSSPVKAG V ETTTPSKQ ...String:
YELTQPPSVS VAPGKTARIT CGGKDLGSKS VHWYQQKPGQ APVLVIYYDN IRPSGIPERF SGSNSGNTAT LTISRVEAGD EADYYCQVW DSSSDHYVFG RGAKVTVLGQ PKAAPSVTLF PPSSEELQAN KATLVCLISD FYPGAVTVAW KADSSPVKAG V ETTTPSKQ SNNKYAASSY LSLTPEQWKS HRSYSCQVTH EGSTVEKTVA PTECS

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Macromolecule #4: RUPA58 Fab Light Chain

MacromoleculeName: RUPA58 Fab Light Chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.355043 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: IQMTQSPSSL SASVGDRVTI TCRASQIIST YLNWYQHKPG KAPKLLIKSA STLQSGVPSR FSGSGSGTDF TLTITSLQPE DFATFYCQQ SYRDPITFGQ GTRLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ E SVTEQDSK ...String:
IQMTQSPSSL SASVGDRVTI TCRASQIIST YLNWYQHKPG KAPKLLIKSA STLQSGVPSR FSGSGSGTDF TLTITSLQPE DFATFYCQQ SYRDPITFGQ GTRLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ E SVTEQDSK DSTYSLSSTL TLSKADYEKH KVYACEVTHQ GLSSPVTKSF NRGEC

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Macromolecule #5: RUPA58 Fab Heavy Chain

MacromoleculeName: RUPA58 Fab Heavy Chain / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.416352 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QVQLVQSGPE AKKPGASVKV SCQASGYPFS GYYMHWLRQA PGQGLEWMGW MNPNSGGTKY AQRFQGRVTM TRDTSISTAH MELRGLRSD DTAVYYCARD YCTGSSCYRT DYDYWGQGTL VTVSSASTKG PSVFPLAPSS KSTSGGTAAL GCLVKDYFPE P VTVSWNSG ...String:
QVQLVQSGPE AKKPGASVKV SCQASGYPFS GYYMHWLRQA PGQGLEWMGW MNPNSGGTKY AQRFQGRVTM TRDTSISTAH MELRGLRSD DTAVYYCARD YCTGSSCYRT DYDYWGQGTL VTVSSASTKG PSVFPLAPSS KSTSGGTAAL GCLVKDYFPE P VTVSWNSG ALTSGVHTFP AVLQSSGLYS LSSVVTVPSS SLGTQTYICN VNHKPSNTKV DKKVEPKSC

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Macromolecule #7: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 7 / Number of copies: 1 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

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

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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

Concentration0.5 mg/mL
BufferpH: 7
Component:
ConcentrationFormulaName
50.0 mM2-Amino-2-(hydroxymethyl)propane-1,3-diolTris-buffered saline
150.0 mMNaClSodium chloride
GridModel: Homemade / Material: GOLD / Mesh: 400 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 15 sec. / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber humidity: 90 % / Chamber temperature: 277 K / Instrument: LEICA EM GP
Details: sample was frozen with Leica Automatic Plunge Freezer EM GP2.

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Number real images: 7744 / Average exposure time: 8.83 sec. / Average electron dose: 48.69 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.5 µm / Nominal magnification: 75000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 6424191
CTF correctionSoftware - Name: cryoSPARC (ver. 4) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4)
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
Number images used: 306744
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE

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Atomic model buiding 1

Initial model
PDB IDChain

7zxg

chain_id: A, source_name: PDB, initial_model_type: experimental model

8u70

chain_id: B, source_name: PDB, initial_model_type: experimental model

8u70

chain_id: C, source_name: PDB, initial_model_type: experimental model
RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-8u1p:
Local refinement of Plasmodium falciparum gametocyte surface protein Pfs48/45 Domains 1 and 2 in complex with neutralizing antibodies

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