The malarial aspartic proteinases (plasmepsins) have been discovered in several 
species of Plasmodium, including all four of the human malarial pathogens. In 
P.falciparum, plasmepsins I, II, IV and HAP have been directly implicated in 
hemoglobin degradation during malaria infection, and are now considered targets 
for anti-malarial drug design. The plasmepsins are produced from inactive 
zymogens, proplasmepsins, having unusually long N-terminal prosegments of more 
than 120 amino acids. Structural and biochemical evidence suggests that the 
conversion process of proplasmepsins to plasmepsins differs substantially from 
the gastric and plant aspartic proteinases. Instead of blocking substrate access 
to a pre-formed active site, the prosegment enforces a conformation in which 
proplasmepsin cannot form a functional active site. We have determined crystal 
structures of plasmepsin and proplasmepsin from P.vivax. The three-dimensional 
structure of P.vivax plasmepsin is typical of the monomeric aspartic 
proteinases, and the structure of P.vivax proplasmepsin is similar to that of 
P.falciparum proplasmepsin II. A dramatic refolding of the mature N terminus and 
a large (18 degrees ) reorientation of the N-domain between P.vivax 
proplasmepsin and plasmepsin results in a severe distortion of the active site 
region of the zymogen relative to that of the mature enzyme. The present 
structures confirm that the mode of inactivation observed originally in 
P.falciparum proplasmepsin II, i.e. an incompletely formed active site, is a 
true structural feature and likely represents the general mode of inactivation 
of the related proplasmepsins.