3NRR

Co-crystal structure of dihydrofolate reductase-thymidylate synthase from Babesia bovis with dUMP, Raltitrexed and NADP

Summary for 3NRR

• Entry DOI: 10.2210/pdb3nrr/pdb
• Related: 3i3r 3k2h
• Descriptor: Dihydrofolate reductase-thymidylate synthase, CHLORIDE ION, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (9 entities in total)
• Functional Keywords: structural genomics, seattle structural genomics center for infectious disease, ssgcid, niaid, dihydrofolate reductase, thymidylate synthase, dhfr, ts, thya, oxidoreductase, methyltransferase, babesiosis, dump, nadp, raltitrexed, tomudex, transferase
• Biological source: Babesia bovis
• Total number of polymer chains: 2
• Total formula weight: 122165.90

Authors

Seattle Structural Genomics Center for Infectious Disease (SSGCID) (deposition date: 2010-06-30, release date: 2010-07-14, Last modification date: 2023-09-06)

Primary citation

Begley, D.W.,Edwards, T.E.,Raymond, A.C.,Smith, E.R.,Hartley, R.C.,Abendroth, J.,Sankaran, B.,Lorimer, D.D.,Myler, P.J.,Staker, B.L.,Stewart, L.J.
Inhibitor-bound complexes of dihydrofolate reductase-thymidylate synthase from Babesia bovis.
Acta Crystallogr.,Sect.F, 67:1070-1077, 2011

PubMed 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.

PubMed: 21904052
DOI: 10.1107/S1744309111029009

Experimental method

X-RAY DIFFRACTION (1.8 Å)