Ezra T. Bekkering, Randy Yoo, Sophia Hailemariam, Fabian Heide, Danton Ivanochko, Matthew R. Jackman, Nicholas I. Proellochs, Rianne Stoter, Geert-Jan van Gemert, Ayana Maeda, Takaaki Yuguchi, Oscar T. Wanders, Renate C. van Daalen, Maartje R. Inklaar, Carolina M. Andrade, Pascal W.T.C. Jansen, Michiel Vermeulen, Teun Bousema, Eizo Takashima, John L. Rubinstein, Taco W. A. Kooij, Matthijs M. Jore, Jean‐Philippe Julien
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.