期刊
NATURE STRUCTURAL & MOLECULAR BIOLOGY
卷 22, 期 7, 页码 532-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.3048
关键词
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资金
- PATH-Malaria Vaccine Initiative
- Bloomberg Family Foundation through the Johns Hopkins Malaria Research Institute
- Johns Hopkins Malaria Research Institute predoctoral fellow
- Calvin and Helen Lang Postdoctoral Fellow in the Biological Sciences
- Institut de Recherche pour le Developpement Fellowship
- Ifakara Health Institute
- Australian National Health and Medical Research Council Early Career Fellowship [1072267]
- Medical Research Council Early Career Fellowship [1072267]
- Australian Research Council Future Fellowship [110100223]
- National Health and Medical Research Council of Australia [1072267] Funding Source: NHMRC
Mosquito-based malaria transmission-blocking vaccines (mTBVs) target midgut-surface antigens of the Plasmodium parasite's obligate vector, the Anopheles mosquito. The alanyl aminopeptidase N (AnAPN1) is the leading mTBV immunogen; however, AnAPN1's role in Plasmodium infection of the mosquito and how anti-AnAPN1 antibodies functionally block parasite transmission have remained elusive. Here we present the 2.65-angstrom crystal structure of AnAPN1 and the immunoreactivity and transmission-blocking profiles of three monoclonal antibodies (mAbs) to AnAPN1, including mAb 4H5B7, which effectively blocks transmission of natural strains of Plasmodium falciparum. Using the AnAPN1 structure, we map the conformation-dependent 4H5B7 neoepitope to a previously uncharacterized region on domain 1 and further demonstrate that nonhuman-primate neoepitope-specific IgG also blocks parasite transmission. We discuss the prospect of a new biological function of AnAPN1 as a receptor for Plasmodium in the mosquito midgut and the implications for redesigning the AnAPN1 mTBV.
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