1TSL

L. CASEI THYMIDYLATE SYNTHASE WITH SPECIES SPECIFIC INHIBITOR

Summary for 1TSL

• Entry DOI: 10.2210/pdb1tsl/pdb
• Descriptor: THYMIDYLATE SYNTHASE, PHOSPHATE ION, 3'-3"-DICHLOROPHENOL-1,8-3H-BENZO[DE]ISOCHROMEN-1-ONE, ... (4 entities in total)
• Functional Keywords: methyltransferase, species specificity, structure-based drug design, antibiotic
• Biological source: Lactobacillus casei
• Cellular location: Cytoplasm: P00469
• Total number of polymer chains: 1
• Total formula weight: 37162.70

Authors

Stout, T.J.,Stroud, R.M. (deposition date: 1997-06-12, release date: 1998-06-17, Last modification date: 2024-05-22)

Primary citation

Stout, T.J.,Tondi, D.,Rinaldi, M.,Barlocco, D.,Pecorari, P.,Santi, D.V.,Kuntz, I.D.,Stroud, R.M.,Shoichet, B.K.,Costi, M.P.
Structure-based design of inhibitors specific for bacterial thymidylate synthase.
Biochemistry, 38:1607-1617, 1999

PubMed Abstract: Thymidylate synthase is an attractive target for antiproliferative drug design because of its key role in the synthesis of DNA. As such, the enzyme has been widely targeted for anticancer applications. In principle, TS should also be a good target for drugs used to fight infectious disease. In practice, TS is highly conserved across species, and it has proven to be difficult to develop inhibitors that are selective for microbial TS enzymes over the human enzyme. Using the structure of TS from Lactobacillus casei in complex with the nonsubstrate analogue phenolphthalein, inhibitors were designed to take advantage of features of the bacterial enzyme that differ from those of the human enzyme. Upon synthesis and testing, these inhibitors were found to be up to 40-fold selective for the bacterial enzyme over the human enzyme. The crystal structures of two of these inhibitors in complex with TS suggested the design of further compounds. Subsequent synthesis and testing showed that these second-round compounds inhibit the bacterial enzyme at sub-micromolar concentrations, while the human enzyme was not inhibited at detectable levels (selectivities of 100-1000-fold or greater). Although these inhibitors share chemical similarities, X-ray crystal structures reveal that the analogues bind to the enzyme in substantially different orientations. Site-directed mutagenesis experiments suggest that the individual inhibitors may adopt multiple configurations in their complexes with TS.

PubMed: 9931028
DOI: 10.1021/bi9815896

Experimental method

X-RAY DIFFRACTION (2.5 Å)