Structure of endogenous Pfs230:Pfs48/45 in complex with potent malaria transmission-blocking antibodies.

Abstract

The Pfs230:Pfs48/45 complex is essential for malaria parasites to infect mosquitoes and forms the basis for current leading transmission-blocking vaccine candidates, yet little is known about its molecular assembly. Here, we used cryogenic electron microscopy to elucidate the structure of the endogenous Pfs230:Pfs48/45 complex bound to six potent transmission-blocking antibodies. Pfs230 consists of multiple domain clusters rigidified by interactions mediated through insertion domains. Membrane-anchored Pfs48/45 forms a disc-like structure and interacts with a short C-terminal peptide on Pfs230 that is critical for Pfs230 membrane-retention in vivo. Analyses of Pfs48/45- and Pfs230-targeted antibodies identify conserved epitopes on the Pfs230:Pfs48/45 complex and provides a structural paradigm for complement-dependent activity of Pfs230-targeting antibodies. Altogether, the Pfs230:Pfs48/45 antibody-complex structure presented improves our understanding of malaria transmission biology and the mechanisms of action of transmission-blocking antibodies, informing the development of next-generation transmission-blocking interventions.