9N7K

Crystal structure of human anti-Pfs48/45 transmission-blocking antibody RUPA-71

Summary for 9N7K

• Entry DOI: 10.2210/pdb9n7k/pdb
• Descriptor: RUPA-71 Fab heavy chain, RUPA-71 Fab kappa chain, GLYCEROL, ... (5 entities in total)
• Functional Keywords: pfs48/45, human transmission-blocking antibodies, malaria, immune system
• Biological source: Homo sapiens; More
• Total number of polymer chains: 4
• Total formula weight: 97422.80

Authors

Hailemariam, S.,Ivanochko, D.,Liu, X.,Julien, J.P. (deposition date: 2025-02-06, release date: 2025-10-15, Last modification date: 2025-11-26)

Primary citation

Bekkering, E.T.,Yoo, R.,Hailemariam, S.,Heide, F.,Ivanochko, D.,Jackman, M.,Proellochs, N.I.,Stoter, R.,van Gemert, G.J.,Maeda, A.,Yuguchi, T.,Wanders, O.T.,van Daalen, R.C.,Inklaar, M.R.,Andrade, C.M.,Jansen, P.W.T.C.,Vermeulen, M.,Bousema, T.,Takashima, E.,Rubinstein, J.L.,Kooij, T.W.A.,Jore, M.M.,Julien, J.P.
Cryo-EM structure of endogenous Pfs230:Pfs48/45 complex with six antibodies reveals mechanisms of malaria transmission-blocking activity.
Immunity, 58:2899-, 2025

PubMed Abstract: The Pfs230:Pfs48/45 complex forms the basis for leading malaria transmission-blocking vaccine candidates, yet little is known about its molecular assembly. Here, we used cryo-electron microscopy to elucidate the structure of the endogenous Pfs230:Pfs48/45 complex bound to six transmission-blocking antibodies. Our structure revealed that Pfs230 consists of multiple domain clusters rigidified by interactions mediated through insertion domains. Membrane-anchored Pfs48/45 formed a disk-like structure, interacting with a short C-terminal peptide on Pfs230 that was critical for Pfs230 membrane-retention in vivo. Membrane retention through this interaction was not essential for transmission to mosquitoes, suggesting that complex disruption is not a mode of action for transmission-blocking antibodies. Analyses of Pfs48/45- and Pfs230-targeted antibodies identified conserved epitopes on the Pfs230:Pfs48/45 complex and provided a structural paradigm for complement-dependent activity of Pfs230-targeting antibodies. Altogether, the antibody-bound Pfs230:Pfs48/45 structure improves our molecular understanding of this biological complex, informing the development of next-generation Plasmodium falciparum transmission-blocking interventions.

PubMed: 41072404
DOI: 10.1016/j.immuni.2025.09.014

Experimental method

X-RAY DIFFRACTION (2.28 Å)