{"doi":"10.1016/j.immuni.2025.09.014","title":"Cryo-EM structure of endogenous Pfs230:Pfs48/45 complex with six antibodies reveals mechanisms of malaria transmission-blocking activity","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.","journal":"Immunity","year":2025,"id":514966,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.95,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1178404,"name":"Randy Yoo","orcid":"0000-0002-6952-9039","position":1,"is_corresponding":false},{"id":860977,"name":"Sophia Hailemariam","orcid":"0000-0002-5999-4244","position":2,"is_corresponding":false},{"id":1147635,"name":"Fabian Heide","orcid":"0000-0002-6849-3177","position":3,"is_corresponding":false},{"id":829516,"name":"Danton Ivanochko","orcid":"0000-0002-2826-8100","position":4,"is_corresponding":false},{"id":395395,"name":"Matthew R. 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Andrade","orcid":"0000-0002-9763-8857","position":14,"is_corresponding":false},{"id":79068,"name":"Pascal W.T.C. Jansen","orcid":"0000-0003-3064-5742","position":15,"is_corresponding":false},{"id":79067,"name":"Michiel Vermeulen","orcid":"0000-0003-0836-6894","position":16,"is_corresponding":false},{"id":262843,"name":"Teun Bousema","orcid":"0000-0003-2666-094X","position":17,"is_corresponding":false},{"id":339354,"name":"Eizo Takashima","orcid":"0000-0001-9070-8499","position":18,"is_corresponding":false},{"id":98514,"name":"John L. Rubinstein","orcid":"0000-0003-0566-2209","position":19,"is_corresponding":false},{"id":870851,"name":"Taco W. A. Kooij","orcid":"0000-0002-8547-7523","position":20,"is_corresponding":false},{"id":455393,"name":"Matthijs M. Jore","orcid":"0000-0002-0686-370X","position":21,"is_corresponding":false},{"id":331370,"name":"Jean‐Philippe Julien","orcid":"0000-0001-7602-3995","position":22,"is_corresponding":false},{"id":1378397,"name":"Ezra T. 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