Inhibitor-bound complexes of dihydrofolate reductase-thymidylate synthase from Babesia bovis

Begley, Darren W.; Edwards, Thomas E.; Raymond, Amy C.; Smith, Eric R.; Hartley, Robert C.; Abendroth, Jan; Sankaran, Banumathi; Lorimer, Donald D.; Myler, Peter J.; Staker, Bart L.; Stewart, Lance J.

doi:10.1107/s1744309111029009

Title: Inhibitor-bound complexes of dihydrofolate reductase-thymidylate synthase from Babesia bovis

Journal Article · Tue Aug 16 00:00:00 EDT 2011 · Acta Crystallographica. Section F

DOI:https://doi.org/10.1107/s1744309111029009· OSTI ID:1625813

Begley, Darren W. ^[1]; Edwards, Thomas E. ^[2]; Raymond, Amy C. ^[2]; Smith, Eric R. ^[2]; Hartley, Robert C. ^[2]; Abendroth, Jan ^[2]; Sankaran, Banumathi ^[3]; Lorimer, Donald D. ^[2]; Myler, Peter J. ^[4]; Staker, Bart L. ^[2]; Stewart, Lance J. ^[2]

Seattle Structural Genomics Center for Infectious Disease, Seattle, WA (United States); Emerald BioStructures Inc., Bainbridge Island, WA (United States)
Seattle Structural Genomics Center for Infectious Disease, Seattle, WA (United States); Emerald BioStructures Inc., Bainbridge Island, WA (United States)
Berkeley Center for Structural Biology, Berkeley, CA (United States)
Seattle Structural Genomics Center for Infectious Disease, Seattle, WA (United States); Seattle BioMed, Seattle, WA (United States); Univ. of Washington, Seattle, WA (United States). School of Medicine. Depts. of Global Health, Medical Education and Biomedical Informatics

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 reductasethymidylate 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.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1625813

Journal Information:: Acta Crystallographica. Section F, Vol. 67, Issue 9; ISSN 1744-3091

Publisher:: International Union of CrystallographyCopyright Statement

Country of Publication:: United States

Language:: English

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Title: Inhibitor-bound complexes of dihydrofolate reductase-thymidylate synthase from Babesia bovis

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