8G6B

Crystal structure of PfAMA1-RON2L chimera

Summary for 8G6B

• Entry DOI: 10.2210/pdb8g6b/pdb
• Descriptor: Apical membrane antigen 1, rhoptry neck protein 2 chimera, SULFATE ION (3 entities in total)
• Functional Keywords: parasite invasion, moving junction, membrane protein
• Biological source: Plasmodium falciparum 3D7
• Total number of polymer chains: 2
• Total formula weight: 82939.08

Authors

Boulanger, M.J.,Ramaswamy, R. (deposition date: 2023-02-14, release date: 2023-09-13, Last modification date: 2024-10-09)

Primary citation

Yanik, S.,Venkatesh, V.,Parker, M.L.,Ramaswamy, R.,Diouf, A.,Sarkar, D.,Miura, K.,Long, C.A.,Boulanger, M.J.,Srinivasan, P.
Structure guided mimicry of an essential P. falciparum receptor-ligand complex enhances cross neutralizing antibodies.
Nat Commun, 14:5879-5879, 2023

PubMed Abstract: Invasion of human erythrocytes by Plasmodium falciparum (Pf) merozoites relies on the interaction between two parasite proteins: apical membrane antigen 1 (AMA1) and rhoptry neck protein 2 (RON2). While antibodies to AMA1 provide limited protection against Pf in non-human primate malaria models, clinical trials using recombinant AMA1 alone (apoAMA1) yielded no protection due to insufficient functional antibodies. Immunization with AMA1 bound to RON2L, a 49-amino acid peptide from its ligand RON2, has shown superior protection by increasing the proportion of neutralizing antibodies. However, this approach relies on the formation of a complex in solution between the two vaccine components. To advance vaccine development, here we engineered chimeric antigens by replacing the AMA1 DII loop, displaced upon ligand binding, with RON2L. Structural analysis confirmed that the fusion chimera (Fusion-F) closely mimics the binary AMA1-RON2L complex. Immunization studies in female rats demonstrated that Fusion-F immune sera, but not purified IgG, neutralized vaccine-type parasites more efficiently compared to apoAMA1, despite lower overall anti-AMA1 titers. Interestingly, Fusion-F immunization enhanced antibodies targeting conserved epitopes on AMA1, leading to increased neutralization of non-vaccine type parasites. Identifying these cross-neutralizing antibody epitopes holds promise for developing an effective, strain-transcending malaria vaccine.

PubMed: 37735574
DOI: 10.1038/s41467-023-41636-5

Experimental method

X-RAY DIFFRACTION (1.55 Å)