1tsm

L. CASEI THYMIDYLATE SYNTHASE WITH SPECIES SPECIFIC INHIBITOR

spinqualitylabelsall models 1tsm, resolution 3.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 1tsm is a 1 chain structure with sequence from Lactobacillus casei. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: MR2, PO4 Activity: Thymidylate synthase, with EC number 2.1.1.45 Resources: FirstGlance, OCA, RCSB, PDBsum Function [TYSY_LACCA] Provides the sole de novo source of dTMP for DNA biosynthesis. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed 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. Structure-based design of inhibitors specific for bacterial thymidylate synthase.,Stout TJ, Tondi D, Rinaldi M, Barlocco D, Pecorari P, Santi DV, Kuntz ID, Stroud RM, Shoichet BK, Costi MP Biochemistry. 1999 Feb 2;38(5):1607-17. PMID:9931028 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Thymidylate synthase

Proteopedia Page Contributors and Editors (what is this?)

OCA