Babesiosis is a tick-borne disease caused by eukaryotic Babesia parasites which 
are morphologically similar to Plasmodium falciparum, the causative agent of 
malaria in humans. Like Plasmodium, different species of Babesia are tuned to 
infect different mammalian hosts, including rats, dogs, horses and cattle. Most 
species of Plasmodium and Babesia possess an essential bifunctional enzyme for 
nucleotide synthesis and folate metabolism: dihydrofolate reductase-thymidylate 
synthase. Although thymidylate synthase is highly conserved across organisms, 
the bifunctional form of this enzyme is relatively uncommon in nature. The 
structural characterization of dihydrofolate reductase-thymidylate synthase in 
Babesia bovis, the causative agent of babesiosis in livestock cattle, is 
reported here. The apo state is compared with structures that contain dUMP, NADP 
and two different antifolate inhibitors: pemetrexed and raltitrexed. The 
complexes reveal modes of binding similar to that seen in drug-resistant malaria 
strains and point to the utility of applying structural studies with proven 
cancer chemotherapies towards infectious disease research.