1tsm: Difference between revisions
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==Overview== | ==Overview== | ||
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 ... | 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. | ||
==About this Structure== | ==About this Structure== | ||
1TSM is a | 1TSM is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Lactobacillus_casei Lactobacillus casei] with PO4 and MR2 as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Thymidylate_synthase Thymidylate synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.45 2.1.1.45] Structure known Active Site: CAT. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1TSM OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: structure-based drug design]] | [[Category: structure-based drug design]] | ||
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Revision as of 14:25, 5 November 2007
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L. CASEI THYMIDYLATE SYNTHASE WITH SPECIES SPECIFIC INHIBITOR
OverviewOverview
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.
About this StructureAbout this Structure
1TSM is a Single protein structure of sequence from Lactobacillus casei with PO4 and MR2 as ligands. Active as Thymidylate synthase, with EC number 2.1.1.45 Structure known Active Site: CAT. Full crystallographic information is available from OCA.
ReferenceReference
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
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