Plasmodium falciparum is the major causative agent of malaria, a disease of 
worldwide importance. Resistance to current drugs such as chloroquine and 
mefloquine is spreading at an alarming rate, and our antimalarial armamentarium 
is almost depleted. The malarial parasite encodes two homologous aspartic 
proteases, plasmepsins I and II, which are essential components of its 
hemoglobin-degradation pathway and are novel targets for antimalarial drug 
development. We have determined the crystal structure of recombinant plasmepsin 
II complexed with pepstatin A. This represents the first reported crystal 
structure of a protein from P. falciparum. The crystals contain molecules in two 
different conformations, revealing a remarkable degree of interdomain 
flexibility of the enzyme. The structure was used to design a series of 
selective low molecular weight compounds that inhibit both plasmepsin II and the 
growth of P. falciparum in culture.