2QK8

Crystal structure of the anthrax drug target, Bacillus anthracis dihydrofolate reductase

Summary for 2QK8

• Entry DOI: 10.2210/pdb2qk8/pdb
• Descriptor: Dihydrofolate reductase, METHOTREXATE (3 entities in total)
• Functional Keywords: oxidoreductase, methotrexate, pteridine binding, nucleotide phosphate binding, pseudo-rossman fold
• Biological source: Bacillus anthracis str.
• Total number of polymer chains: 1
• Total formula weight: 19603.29

Authors

Bennett, B.C.,Xu, H.,Simmerman, R.F.,Lee, R.E.,Dealwis, C.G. (deposition date: 2007-07-10, release date: 2007-08-28, Last modification date: 2023-08-30)

Primary citation

Bennett, B.C.,Xu, H.,Simmerman, R.F.,Lee, R.E.,Dealwis, C.G.
Crystal structure of the anthrax drug target, Bacillus anthracis dihydrofolate reductase.
J.Med.Chem., 50:4374-4381, 2007

PubMed Abstract: 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 Angstrom 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.

PubMed: 17696333
DOI: 10.1021/jm070319v

Experimental method

X-RAY DIFFRACTION (2.4 Å)