Solution structure of a brodimoprim analogue in its complex with Lactobacillus casei dihydrofolate reductase

Biochemistry
W D MorganJ Feeney

Abstract

Two-dimensional (2D) double-quantum-filtered correlation spectroscopy (DQF-COSY), total correlation spectroscopy (TOCSY), nuclear Overhauser effect spectroscopy (NOESY), and rotating-frame NOESY (ROESY) spectra were used to assign essentially all the protons in a 1:1 complex of Lactobacillus casei dihydrofolate reductase formed with an analogue of the antibacterial drug brodimoprim [2,4-diamino-5-(3',5'-dimethoxy-4'-bromobenzyl)pyrimidine]. The analogue has a 4,6-dicarboxylic acid side chain substituted on the 3'-O position designed to interact with the Arg 57 and His 28 residues in L. casei dihydrofolate reductase; it binds a factor of 10(3) more tightly to the enzyme than does the parent compound. Thirty-eight intermolecular and 11 intramolecular NOEs were measured involving the bound brodimoprim-4,6-dicarboxylic acid analogue. These provided the distance constraints used in conjunction with an energy minimization and simulated annealing protocol (using Discover from Biosym Ltd.) to dock the brodimoprim analogue into dihydrofolate reductase. In calculations where side chains and backbone fragments for binding-site residues were allowed flexibility, 90% of the 40 calculated structures had reasonable covalent geometry and none ...Continue Reading

Citations

Aug 12, 2009·Journal of Biomolecular NMR·David H JonesBernhard H Geierstanger
Nov 19, 2003·Bioorganic & Medicinal Chemistry Letters·Peter SchneiderKhalid Islam
Feb 27, 1999·Current Opinion in Biotechnology·G C Roberts
Aug 14, 2003·Journal of Magnetic Resonance·Jiangli YanEdward R Zartler
Mar 28, 2003·Proteins·Diane Joseph-McCarthyJuan C Alvarez
Aug 22, 2002·Journal of the American Chemical Society·Jiangli YanMichael J Shapiro

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