Cryo-EM structure of an essential Plasmodium vivaxinvasion complex

Plasmodium vivaxis the most widely distributed malaria parasite that infects humans1. P. vivaxinvades reticulocytes exclusively, and successful entry depends on specific interactions between the P. vivaxreticulocyte-binding protein 2b (PvRBP2b) and transferrin receptor 1 (TfR1)2. TfR1-deficient erythroid cells are refractory to invasion by P. vivax, and anti-PvRBP2b monoclonal antibodies inhibit reticulocyte binding and block P. vivaxinvasion in field isolates2. Here we report a high-resolution cryo-electron microscopy structure of a ternary complex of PvRBP2b bound to human TfR1 and transferrin, at 3.7 Å resolution. Mutational analyses show that PvRBP2b residues involved in complex formation are conserved; this suggests that antigens could be designed that act across P. vivaxstrains. Functional analyses of TfR1 highlight how P. vivaxhijacks TfR1, an essential housekeeping protein, by binding to sites that govern host specificity, without affecting its cellular function of transporting iron. Crystal and solution structures of PvRBP2b in complex with antibody fragments characterize the inhibitory epitopes. Our results establish a structural framework for understanding how P. vivaxreticulocyte-binding protein engages its receptor and the molecular mechanism of inhibitory monoclonal antibodies, providing important information for the design of novel vaccine candidates. Structural studies show that conserved residues in Plasmodium vivaxreticulocyte-binding protein 2b determine interactions with transferrin receptor 1 that are essential for host invasion, suggesting avenues for designing vaccines that work across P. vivaxstrains.