1f4c

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[[Image:1f4c.jpg|left|200px]]
 
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==CRYSTAL STRUCTURE OF E. COLI THYMIDYLATE SYNTHASE COVALENTLY MODIFIED AT C146 WITH N-[TOSYL-D-PROLINYL]AMINO-ETHANETHIOL==
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The line below this paragraph, containing "STRUCTURE_1f4c", creates the "Structure Box" on the page.
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<StructureSection load='1f4c' size='340' side='right'caption='[[1f4c]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
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== Structural highlights ==
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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<table><tr><td colspan='2'>[[1f4c]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1F4C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1F4C FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CXM:N-CARBOXYMETHIONINE'>CXM</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=TP2:N-[TOSYL-D-PROLINYL]AMINO-ETHANETHIOL'>TP2</scene></td></tr>
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{{STRUCTURE_1f4c| PDB=1f4c | SCENE= }}
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1f4c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1f4c OCA], [https://pdbe.org/1f4c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1f4c RCSB], [https://www.ebi.ac.uk/pdbsum/1f4c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1f4c ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/TYSY_ECOLI TYSY_ECOLI] Provides the sole de novo source of dTMP for DNA biosynthesis. This protein also binds to its mRNA thus repressing its own translation.
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/f4/1f4c_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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/main_output.php?pdb_ID=1f4c ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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We report a strategy (called "tethering") to discover low molecular weight ligands ( approximately 250 Da) that bind weakly to targeted sites on proteins through an intermediary disulfide tether. A native or engineered cysteine in a protein is allowed to react reversibly with a small library of disulfide-containing molecules ( approximately 1,200 compounds) at concentrations typically used in drug screening (10 to 200 microM). The cysteine-captured ligands, which are readily identified by MS, are among the most stable complexes, even though in the absence of the covalent tether the ligands may bind very weakly. This method was applied to generate a potent inhibitor for thymidylate synthase, an essential enzyme in pyrimidine metabolism with therapeutic applications in cancer and infectious diseases. The affinity of the untethered ligand (K(i) approximately 1 mM) was improved 3,000-fold by synthesis of a small set of analogs with the aid of crystallographic structures of the tethered complex. Such site-directed ligand discovery allows one to nucleate drug design from a spatially targeted lead fragment.
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'''CRYSTAL STRUCTURE OF E. COLI THYMIDYLATE SYNTHASE COVALENTLY MODIFIED AT C146 WITH N-[TOSYL-D-PROLINYL]AMINO-ETHANETHIOL'''
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Site-directed ligand discovery.,Erlanson DA, Braisted AC, Raphael DR, Randal M, Stroud RM, Gordon EM, Wells JA Proc Natl Acad Sci U S A. 2000 Aug 15;97(17):9367-72. PMID:10944209<ref>PMID:10944209</ref>
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==Overview==
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We report a strategy (called "tethering") to discover low molecular weight ligands ( approximately 250 Da) that bind weakly to targeted sites on proteins through an intermediary disulfide tether. A native or engineered cysteine in a protein is allowed to react reversibly with a small library of disulfide-containing molecules ( approximately 1,200 compounds) at concentrations typically used in drug screening (10 to 200 microM). The cysteine-captured ligands, which are readily identified by MS, are among the most stable complexes, even though in the absence of the covalent tether the ligands may bind very weakly. This method was applied to generate a potent inhibitor for thymidylate synthase, an essential enzyme in pyrimidine metabolism with therapeutic applications in cancer and infectious diseases. The affinity of the untethered ligand (K(i) approximately 1 mM) was improved 3,000-fold by synthesis of a small set of analogs with the aid of crystallographic structures of the tethered complex. Such site-directed ligand discovery allows one to nucleate drug design from a spatially targeted lead fragment.
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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1F4C is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1F4C OCA].
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</div>
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<div class="pdbe-citations 1f4c" style="background-color:#fffaf0;"></div>
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==Reference==
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==See Also==
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Site-directed ligand discovery., Erlanson DA, Braisted AC, Raphael DR, Randal M, Stroud RM, Gordon EM, Wells JA, Proc Natl Acad Sci U S A. 2000 Aug 15;97(17):9367-72. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/10944209 10944209]
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*[[Thymidylate synthase 3D structures|Thymidylate synthase 3D structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Escherichia coli]]
[[Category: Escherichia coli]]
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[[Category: Single protein]]
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[[Category: Large Structures]]
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[[Category: Thymidylate synthase]]
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[[Category: Braisted AC]]
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[[Category: Braisted, A C.]]
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[[Category: Erlanson DA]]
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[[Category: Erlanson, D A.]]
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[[Category: Gordon E]]
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[[Category: Gordon, E.]]
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[[Category: Randal M]]
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[[Category: Randal, M.]]
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[[Category: Raphael DR]]
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[[Category: Raphael, D R.]]
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[[Category: Stroud RM]]
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[[Category: Stroud, R M.]]
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[[Category: Wells JA]]
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[[Category: Wells, J A.]]
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[[Category: E. coli thymidylate synthase modified at cysteine 146]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 15:52:53 2008''
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Current revision

CRYSTAL STRUCTURE OF E. COLI THYMIDYLATE SYNTHASE COVALENTLY MODIFIED AT C146 WITH N-[TOSYL-D-PROLINYL]AMINO-ETHANETHIOL

PDB ID 1f4c

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