2qk8
Crystal structure of the anthrax drug target, Bacillus anthracis dihydrofolate reductase
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OverviewOverview
Spores of Bacillus anthracis are the infectious agent of anthrax. Current, antibiotic treatments are limited due to resistance and patient age, restrictions; thus, additional targets for therapeutic intervention are, needed. One possible candidate is dihydrofolate reductase (DHFR), a, biosynthetic enzyme necessary for anthrax pathogenicity. We determined the, crystal structure of DHFR from B. anthracis (baDHFR) in complex with, methotrexate (MTX; 1) at 2.4 A resolution. The structure reveals the, crucial interactions required for MTX binding and a putative molecular, basis for how baDHFR has natural resistance to trimethoprim (TMP; 2). The, structure also allows insights for designing selective baDHFR inhibitors, that will have weak affinities for the human enzyme. Additionally, we have, found that 5-nitro-6-methylamino-isocytosine (MANIC; 3), which inhibits, another B. anthracis folate synthesis enzyme, dihydropteroate synthase, (DHPS), can also inhibit baDHFR. This provides a starting point for, designing multi-target inhibitors that are less likely to induce drug, resistance.
About this StructureAbout this Structure
2QK8 is a Single protein structure of sequence from Bacillus anthracis with as ligand. Active as Dihydrofolate reductase, with EC number 1.5.1.3 Full crystallographic information is available from OCA.
ReferenceReference
Crystal Structure of the Anthrax Drug Target, Bacillus anthracis Dihydrofolate Reductase., Bennett BC, Xu H, Simmerman RF, Lee RE, Dealwis CG, J Med Chem. 2007 Aug 14;. PMID:17696333
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