3FL8

Crystal structure of B. anthracis dihydrofolate reductase (DHFR) with RAB1, a TMP-dihydrophthalazine derivative

Summary for 3FL8

• Entry DOI: 10.2210/pdb3fl8/pdb
• Related: 2QK8 3E0B 3FL9
• Descriptor: Dihydrofolate reductase, CALCIUM ION, 5-(3,4-dimethoxy-5-{(1E)-3-oxo-3-[(1S)-1-propylphthalazin-2(1H)-yl]prop-1-en-1-yl}benzyl)pyrimidine-2,4-diamine, ... (4 entities in total)
• Functional Keywords: oxidoreductase, pyrimidine, dihydrophthalazine
• Biological source: Bacillus anthracis (anthrax)
• Total number of polymer chains: 8
• Total formula weight: 161136.78

Authors

Bourne, C.R.,Barrow, W.W. (deposition date: 2008-12-18, release date: 2009-04-28, Last modification date: 2023-09-06)

Primary citation

Bourne, C.R.,Bunce, R.A.,Bourne, P.C.,Berlin, K.D.,Barrow, E.W.,Barrow, W.W.
Crystal structure of Bacillus anthracis dihydrofolate reductase with the dihydrophthalazine-based trimethoprim derivative RAB1 provides a structural explanation of potency and selectivity.
Antimicrob.Agents Chemother., 53:3065-3073, 2009

PubMed Abstract: Bacillus anthracis possesses an innate resistance to the antibiotic trimethoprim due to poor binding to dihydrofolate reductase (DHFR); currently, there are no commercial antibacterials that target this enzyme in B. anthracis. We have previously reported a series of dihydrophthalazine-based trimethoprim derivatives that are inhibitors for this target. In the present work, we have synthesized one compound (RAB1) displaying favorable 50% inhibitory concentration (54 nM) and MIC (< or =12.8 microg/ml) values. RAB1 was cocrystallized with the B. anthracis DHFR in the space group P2(1)2(1)2(1), and X-ray diffraction data were collected to a 2.3-A resolution. Binding of RAB1 causes a conformational change of the side chain of Arg58 and Met37 to accommodate the dihydrophthalazine moiety. Unlike the natural substrate or trimethoprim, the dihydrophthalazine group provides a large hydrophobic anchor that embeds within the DHFR active site and accounts for its selective inhibitory activity against B. anthracis.

PubMed: 19364848
DOI: 10.1128/AAC.01666-08

Experimental method

X-RAY DIFFRACTION (2.2881 Å)