8U1P

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

Summary for 8U1P

• Entry DOI: 10.2210/pdb8u1p/pdb
• Related: 8U70
• EMDB information: 41821 41822
• Descriptor: Gametocyte surface protein P45/48, RUPA154 Fab Heavy Chain, RUPA154 Fab Light Chain, ... (7 entities in total)
• Functional Keywords: transmission blocking vaccine, antibody, malaria, cell invasion, cell invasion-immune system complex, cell invasion/immune system
• Biological source: Plasmodium falciparum 3D7; More
• Total number of polymer chains: 5
• Total formula weight: 142231.35

Authors

Kucharska, I.,Hailemariam, S.,Ivanochko, D.,Rubinstein, J.,Julien, J.P. (deposition date: 2023-09-01, release date: 2025-03-12, Last modification date: 2025-06-04)

Primary citation

Kucharska, I.,Ivanochko, D.,Hailemariam, S.,Inklaar, M.R.,Kim, H.R.,Teelen, K.,Stoter, R.,van de Vegte-Bolmer, M.,van Gemert, G.J.,Semesi, A.,McLeod, B.,Ki, A.,Lee, W.K.,Rubinstein, J.L.,Jore, M.M.,Julien, J.P.
Structural elucidation of full-length Pfs48/45 in complex with potent monoclonal antibodies isolated from a naturally exposed individual.
Nat.Struct.Mol.Biol., 2025

PubMed 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 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.

PubMed: 40404982
DOI: 10.1038/s41594-025-01532-6

Experimental method

ELECTRON MICROSCOPY (3.3 Å)