One promising biological target in Plasmodium falciparum is the essential P-type ATPase PfATP4, which localises to the plasma membrane of the intraerythrocytic parasite and exports Na + while importing H + equivalents . The structure of this membrane-bound protein remains unsolved. Evidence for the involvement if PfATP4 in the mechanism of action of antiplasmodial compounds comes from several sources, including parasite Na + and pH assays that implicated PfATP4 as the target for the spiroindolone cipargamin (currently in Phase III clinical development), the dihydroisoquinolone (+)-SJ733 , and 28 compounds from the Medicines for Malaria Venture (MMV) Malaria Box as well as 11 compounds from the MMV Pathogen Box . These compounds represent a strikingly diverse range of chemotypes (Fig. ) . A homology model of PfATP4 was developed using crystal structures from the closest mammalian homolog, a sarco/endoplasmic reticulum Ca 2+ -ATPase (SERCA) . However, in the absence of a solved structure of PfATP4, ideally bound to small molecule inhibitors, it remains unclear how it is possible for such diverse molecules to share the same target. Indeed, a challenge to understanding such data is that structurally different molecules generating the same phenotype may be interacting with the biological target differently.