Identification of antimalarial drugs and bradykinin as ligands of the Plasmodium membrane protein PfSR10

Malaria caused by <i>Plasmodium falciparum</i> remains a public health issue, yet direct targets of antimalarial drugs remain elusive. Membrane proteins in <i>Plasmodium</i> are potential drug targets and may contribute to pathophysiological processes in malaria. Recent studies show that the serpentine receptor SR10 is essential for coordinating host rhythms during parasite development. In this study, we found that antimalarial drugs including chloroquine (CQ), dihydroartemisinin (DHA), piperaquine-tetraphosphatetetrahydrate (PIP-TT), and primaquine diphosphate (PQ) are PfSR10 agonists that induce coupling with human Gi/Gq proteins, confirmed through biochemical reconstitution and cryo-EM analysis. Using proteomic profiling, we also identified bradykinin as an endogenous agonist activating PfSR10. Ligand binding and conformational changes were characterized via mutagenesis and FlAsH-BRET assays. These results establish PfSR10 as a receptor for both antimalarials and host peptides, highlighting its dual role in drug action and host-parasite communication, with broad implications in understanding malaria pathogenesis and developing new therapeutics.