Dietrich M.H.Chmielewski J.Chan L.J.Tan L.L.Adair A.Lyons F.M.T.Gabriela M.Lopaticki S.Dite T.A.Dagley L.F.Pazzagli L.Gupta P.Kamil M.Vaughan A.M.Rojrung R.Abraham A.Mazhari R.Longley R.J.Zeglinski K.Gouil Q.Mueller I.Fabb S.A.Shandre-Mugan R.Pouton C.W.Glukhova A.Shakeel S.Tham W.H.Mahidol University2025-09-232025-09-232025-09-11Science Vol.389 No.6765 (2025)00368075https://repository.li.mahidol.ac.th/handle/123456789/112185Malaria parasite fertilization occurs in the midgut of a female Anopheles mosquito. Blocking fertilization within the mosquito can prevent malaria transmission. Plasmodium falciparum Pfs230 and Pfs48/45 proteins are critical for male fertility and transmission of the malaria parasite. They form a core fertilization complex, but it is unknown how they interact. We determined a cryo–electron microscopy structure of the endogenous Pfs230-Pfs48/45 complex showing that Pfs48/45 interacts with Pfs230 domains 13 and 14. Transgenic parasite lines with these domains removed were defective in Pfs230 gamete localization and showed reduced oocyst formation. Nanobodies against domains 13 and 14 inhibited Pfs230-Pfs48/45 complex formation and reduced transmission, and structural analyses revealed their epitopes. These Pfs230 domains were targets of naturally acquired immunity and immune sera from messenger RNA lipid nanoparticle immunizations blocked parasite transmission.MultidisciplinaryArticleSCOPUS10.1126/science.ady02412-s2.0-1050155049011095920340743371