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TitleStructural elucidation of full-length Pfs48/45 in complex with potent monoclonal antibodies isolated from a naturally exposed individual.
Journal, issue, pagesNat Struct Mol Biol, Year 2025
Publish dateMay 22, 2025
AuthorsIga 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 /
PubMed AbstractBiomedical 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.
External linksNat Struct Mol Biol / PubMed:40404982
MethodsEM (single particle)
Resolution3.3 - 3.9 Å
Structure data

EMDB-41821: Plasmodium falciparum gametocyte surface protein Pfs48/45 in complex with neutralizing antibodies
Method: EM (single particle) / Resolution: 3.9 Å

EMDB-41822, PDB-8u1p:
Local refinement of Plasmodium falciparum gametocyte surface protein Pfs48/45 Domains 1 and 2 in complex with neutralizing antibodies
Method: EM (single particle) / Resolution: 3.3 Å

Chemicals

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

Source
  • plasmodium falciparum 3d7 (eukaryote)
  • Plasmodium falciparum (malaria parasite P. falciparum)
  • homo sapiens (human)
KeywordsCELL INVASION/Immune System / transmission blocking vaccine / antibody / malaria / CELL INVASION / CELL INVASION-Immune System complex

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