8GIE

Crystal structure of a designed single-component Plasmodium falciparum AMA1-RON2L insertion fusion immunogen 2

Summary for 8GIE

• Entry DOI: 10.2210/pdb8gie/pdb
• Descriptor: Apical membrane antigen 1, rhoptry neck protein 2 chimera (2 entities in total)
• Functional Keywords: single component immunogens, malaria vaccines, cell invasion
• Biological source: Plasmodium falciparum 3D7; More
• Total number of polymer chains: 1
• Total formula weight: 38587.02

Authors

Patel, P.N.,Tolia, N.H. (deposition date: 2023-03-14, release date: 2023-08-30, Last modification date: 2023-09-13)

Primary citation

Patel, P.N.,Dickey, T.H.,Diouf, A.,Salinas, N.D.,McAleese, H.,Ouahes, T.,Long, C.A.,Miura, K.,Lambert, L.E.,Tolia, N.H.
Structure-based design of a strain transcending AMA1-RON2L malaria vaccine.
Nat Commun, 14:5345-5345, 2023

PubMed Abstract: Apical membrane antigen 1 (AMA1) is a key malaria vaccine candidate and target of neutralizing antibodies. AMA1 binds to a loop in rhoptry neck protein 2 (RON2L) to form the moving junction during parasite invasion of host cells, and this complex is conserved among apicomplexan parasites. AMA1-RON2L complex immunization achieves higher growth inhibitory activity than AMA1 alone and protects mice against Plasmodium yoelii challenge. Here, three single-component AMA1-RON2L immunogens were designed that retain the structure of the two-component AMA1-RON2L complex: one structure-based design (SBD1) and two insertion fusions. All immunogens elicited high antibody titers with potent growth inhibitory activity, yet these antibodies did not block RON2L binding to AMA1. The SBD1 immunogen induced significantly more potent strain-transcending neutralizing antibody responses against diverse strains of Plasmodium falciparum than AMA1 or AMA1-RON2L complex vaccination. This indicates that SBD1 directs neutralizing antibody responses to strain-transcending epitopes in AMA1 that are independent of RON2L binding. This work underscores the importance of neutralization mechanisms that are distinct from RON2 blockade. The stable single-component SBD1 immunogen elicits potent strain-transcending protection that may drive the development of next-generation vaccines for improved malaria and apicomplexan parasite control.

PubMed: 37660103
DOI: 10.1038/s41467-023-40878-7

Experimental method

X-RAY DIFFRACTION (1.85 Å)