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Plasmodium falciparum protein Pfs230 D1D2 - Structure of the first two 6-cysteine domains
Structural highlights
FunctionP230_PLAF7 Gametocyte surface protein required for male/female gamete fusion. Also required for male gamete exflagellation and interaction with erythrocytes.[1] Publication Abstract from PubMedTransmission blocking interventions can stop malaria parasite transmission from mosquito to human by inhibiting parasite infection in mosquitos. One of the most advanced candidates for a malaria transmission blocking vaccine is Pfs230. Pfs230 is the largest member of the 6-cysteine protein family with 14 consecutive 6-cysteine domains and is expressed on the surface of gametocytes and gametes. Here, we present the crystal structure of the first two 6-cysteine domains of Pfs230. We identified high affinity Pfs230-specific nanobodies that recognized gametocytes and bind to distinct sites on Pfs230, which were isolated from immunized alpacas. Using two non-overlapping Pfs230 nanobodies, we show that these nanobodies significantly blocked P. falciparum transmission and reduced the formation of exflagellation centers. Crystal structures of the transmission blocking nanobodies with the first 6-cysteine domain of Pfs230 confirm that they bind to different epitopes. In addition, these nanobodies bind to Pfs230 in the absence of the prodomain, in contrast with the binding of known Pfs230 transmission blocking antibodies. These results provide additional structural insight into Pfs230 domains and elucidate a mechanism of action of transmission blocking Pfs230 nanobodies. Nanobodies against Pfs230 block Plasmodium falciparum transmission.,Dietrich MH, Gabriela M, Reaksudsan K, Dixon MWA, Chan LJ, Adair A, Trickey S, O'Neill MT, Tan LL, Lopaticki S, Healer J, Keremane S, Cowman AF, Tham WH Biochem J. 2022 Dec 22;479(24):2529-2546. doi: 10.1042/BCJ20220554. PMID:36520108[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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