9BJH

Crystal structure of neutralizing human monoclonal antibody 75C8 in complex with AMA1 DI-DII

Summary for 9BJH

• Entry DOI: 10.2210/pdb9bjh/pdb
• Descriptor: Apical membrane antigen 1, 75C8 Fab Heavy Chain, 75C8 Fab Light Chain, ... (4 entities in total)
• Functional Keywords: apical membrane antigen 1, ama1, plasmodium, malaria, antigen-antibody complex, structural protein
• Biological source: Plasmodium falciparum 3D7; More
• Total number of polymer chains: 6
• Total formula weight: 179002.24

Authors

Patel, P.N.,Tang, W.K.,Tolia, N.H. (deposition date: 2024-04-25, release date: 2025-03-12, Last modification date: 2025-04-02)

Primary citation

Patel, P.N.,Diouf, A.,Dickey, T.H.,Tang, W.K.,Hopp, C.S.,Traore, B.,Long, C.A.,Miura, K.,Crompton, P.D.,Tolia, N.H.
A strain-transcending anti-AMA1 human monoclonal antibody neutralizes malaria parasites independent of direct RON2L receptor blockade.
Cell Rep Med, 6:101985-101985, 2025

PubMed Abstract: Plasmodium falciparum apical membrane antigen 1 (AMA1) binds a loop in rhoptry neck protein 2 (RON2L) during red cell invasion and is a target for vaccines and therapeutic antibodies against malaria. Here, we report a panel of AMA1-specific naturally acquired human monoclonal antibodies (hmAbs) derived from individuals living in malaria-endemic regions. Two neutralizing hmAbs engage AMA1 independent of the RON2L-binding site. The hmAb 75B10 demonstrates potent strain-transcending neutralization that is independent of RON2L blockade, emphasizing that epitopes outside the RON2L-binding site elicit broad protection against variant parasite strains. The combination of these hmAbs synergistically enhances parasite neutralization. Vaccination with a structure-based design (SBD1) that mimics the AMA1-RON2L complex elicited antibodies similar to the two neutralizing hmAbs connecting vaccination to naturally acquired immunity in humans. The structural definition of a strain-transcending epitope on AMA1 targeted by naturally acquired hmAb establishes paradigms for developing AMA1-based vaccines and therapeutic antibodies.

PubMed: 40020675
DOI: 10.1016/j.xcrm.2025.101985

Experimental method

X-RAY DIFFRACTION (2.8 Å)