View source for 1tsm

==L. CASEI THYMIDYLATE SYNTHASE WITH SPECIES SPECIFIC INHIBITOR==
<StructureSection load='1tsm' size='340' side='right' caption='[[1tsm]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[1tsm]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Lactobacillus_casei Lactobacillus casei]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1TSM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1TSM FirstGlance]. <br>
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MR2:3-DIPHENOL-6-NITRO-3H-BENZO[DE]ISOCHROMEN-1-ONE'>MR2</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene><br>
<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[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] </span></td></tr>
<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1tsm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1tsm OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1tsm RCSB], [http://www.ebi.ac.uk/pdbsum/1tsm PDBsum]</span></td></tr>
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== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ts/1tsm_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
<div style="clear:both"></div>
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== 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<ref>PMID:9931028</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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==See Also==
*[[Thymidylate synthase|Thymidylate synthase]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Lactobacillus casei]]
[[Category: Thymidylate synthase]]
[[Category: Stout, T J.]]
[[Category: Stroud, R M.]]
[[Category: Antibiotic]]
[[Category: Methyltransferase]]
[[Category: Species specificity]]
[[Category: Structure-based drug design]]