7UXL

Crystal structure of malaria transmission-blocking antigen Pfs48/45-6C variant in complex with human antibodies RUPA-44 and RUPA-29

Summary for 7UXL

• Entry DOI: 10.2210/pdb7uxl/pdb
• Descriptor: RUPA-44 Fab Kappa chain, RUPA-44 Fab Heavy chain, Gametocyte surface protein P45/48, ... (6 entities in total)
• Functional Keywords: pfs48/45, human transmission-blocking antibodies, plasmodium falciparum, malaria, immune system
• Biological source: Homo sapiens; More
• Total number of polymer chains: 5
• Total formula weight: 111470.65

Authors

Hailemariam, S.,Ivanochko, D.,Julien, J.P. (deposition date: 2022-05-05, release date: 2023-02-15, Last modification date: 2024-10-16)

Primary citation

Fabra-Garcia, A.,Hailemariam, S.,de Jong, R.M.,Janssen, K.,Teelen, K.,van de Vegte-Bolmer, M.,van Gemert, G.J.,Ivanochko, D.,Semesi, A.,McLeod, B.,Vos, M.W.,de Bruijni, M.H.C.,Bolscher, J.M.,Szabat, M.,Vogt, S.,Kraft, L.,Duncan, S.,Kamya, M.R.,Feeney, M.E.,Jagannathan, P.,Greenhouse, B.,Dechering, K.J.,Sauerwein, R.W.,King, C.R.,MacGill, R.S.,Bousema, T.,Julien, J.P.,Jore, M.M.
Highly potent, naturally acquired human monoclonal antibodies against Pfs48/45 block Plasmodium falciparum transmission to mosquitoes.
Immunity, 56:406-419.e7, 2023

PubMed Abstract: Malaria transmission-blocking vaccines (TBVs) aim to induce antibodies that interrupt malaria parasite development in the mosquito, thereby blocking onward transmission, and provide a much-needed tool for malaria control and elimination. The parasite surface protein Pfs48/45 is a leading TBV candidate. Here, we isolated and characterized a panel of 81 human Pfs48/45-specific monoclonal antibodies (mAbs) from donors naturally exposed to Plasmodium parasites. Genetically diverse mAbs against each of the three domains (D1-D3) of Pfs48/45 were identified. The most potent mAbs targeted D1 and D3 and achieved >80% transmission-reducing activity in standard membrane-feeding assays, at 10 and 2 μg/mL, respectively. Co-crystal structures of D3 in complex with four different mAbs delineated two conserved protective epitopes. Altogether, these Pfs48/45-specific human mAbs provide important insight into protective and non-protective epitopes that can further our understanding of transmission and inform the design of refined malaria transmission-blocking vaccine candidates.

PubMed: 36792574
DOI: 10.1016/j.immuni.2023.01.009

Experimental method

X-RAY DIFFRACTION (2.86 Å)