title: Inhibitor-bound complexes of dihydrofolate reductase-thymidylate synthase from Babesia bovis.
abstract: 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.
authors: Seattle Structural Genomics Center for Infectious Disease (http://www.ssgcid.org), USA. dbegley@embios.com
authors: Darren W
authors: DW
authors: Begley
authors: Thomas E
authors: TE
authors: Edwards
authors: Amy C
authors: AC
authors: Raymond
authors: Eric R
authors: ER
authors: Smith
authors: Robert C
authors: RC
authors: Hartley
authors: Jan
authors: J
authors: Abendroth
authors: Banumathi
authors: B
authors: Sankaran
authors: Donald D
authors: DD
authors: Lorimer
authors: Peter J
authors: PJ
authors: Myler
authors: Bart L
authors: BL
authors: Staker
authors: Lance J
authors: LJ
authors: Stewart
mesh_terms: D001059:Apoproteins / Q000737:chemistry / Q000378:metabolism; D016793:Babesia bovis / Q000201:enzymology*; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D009097:Multienzyme Complexes / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D040681:Structural Homology, Protein; D013379:Substrate Specificity; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry* / Q000378:metabolism; D013940:Thymidylate Synthase / Q000737:chemistry* / Q000378:metabolism
chemical_list: D001059:Apoproteins; D004791:Enzyme Inhibitors; D008024:Ligands; D009097:Multienzyme Complexes; C056930:thymidylate synthase-dihydrofolate reductase; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase