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1tlc

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(New page: 200px<br /><applet load="1tlc" size="450" color="white" frame="true" align="right" spinBox="true" caption="1tlc, resolution 2.1&Aring;" /> '''THYMIDYLATE SYNTHASE ...)
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[[Image:1tlc.gif|left|200px]]<br /><applet load="1tlc" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="1tlc, resolution 2.1&Aring;" />
 
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'''THYMIDYLATE SYNTHASE COMPLEXED WITH DGMP AND FOLATE ANALOG 1843U89'''<br />
 
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==Overview==
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==THYMIDYLATE SYNTHASE COMPLEXED WITH DGMP AND FOLATE ANALOG 1843U89==
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A folate analogue, 1843U89 (U89), with potential as a chemotherapeutic, agent due to its potent and specific inhibition of thymidylate synthase, (TS; EC 2.1.1.45), greatly enhances not only the binding of, 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP) and dUMP to Escherichia, coli TS but also that of dGMP, GMP, dIMP, and IMP. Guanine nucleotide, binding was first detected by CD analysis, which revealed a unique, spectrum for the TS-dGMP-U89 ternary complex. The quantitative binding of, dGMP relative to GMP, FdUMP, and dUMP was determined in the presence and, absence of U89 by ultrafiltration analysis, which revealed that although, the binding of GMP and dGMP could not be detected in the absence of U89, both were bound in its presence. The Kd for dGMP was about the same as, that for dUMP and FdUMP, with binding of the latter two nucleotides being, increased by two orders of magnitude by U89. An explanation for the, binding of dGMP was provided by x-ray diffraction studies that revealed an, extensive stacking interaction between the guanine of dGMP and the, benzoquinazoline ring of U89 and hydrogen bonds similar to those involved, in dUMP binding. In addition, binding energy was provided through a water, molecule that formed hydrogen bonds to both N7 of dGMP and the hydroxyl of, Tyr-94. Accommodation of the larger dGMP molecule was accomplished through, a distortion of the active site and a shift of the deoxyribose moiety to a, new position. These rearrangements also enabled the binding of GMP to, occur by creating a pocket for the ribose 2' hydroxyl group, overcoming, the normal TS discrimination against nucleotides containing the 2', hydroxyl.
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<StructureSection load='1tlc' size='340' side='right'caption='[[1tlc]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1tlc]] 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=1TLC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1TLC 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]] 2.1&#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=DGP:2-DEOXYGUANOSINE-5-MONOPHOSPHATE'>DGP</scene>, <scene name='pdbligand=F89:S)-2-(5(((1,2-DIHYDRO-3-METHYL-1-OXOBENZO(F)QUINAZOLIN-9-YL)METHYL)AMINO)1-OXO-2-ISOINDOLINYL)GLUTARIC+ACID'>F89</scene>, <scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene></td></tr>
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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=1tlc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1tlc OCA], [https://pdbe.org/1tlc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1tlc RCSB], [https://www.ebi.ac.uk/pdbsum/1tlc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1tlc 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/tl/1tlc_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.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=1tlc ConSurf].
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<div style="clear:both"></div>
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==About this Structure==
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==See Also==
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1TLC is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] with DGP and F89 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] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1TLC OCA].
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*[[Thymidylate synthase 3D structures|Thymidylate synthase 3D structures]]
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__TOC__
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==Reference==
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</StructureSection>
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Promotion of purine nucleotide binding to thymidylate synthase by a potent folate analogue inhibitor, 1843U89., Weichsel A, Montfort WR, Ciesla J, Maley F, Proc Natl Acad Sci U S A. 1995 Apr 11;92(8):3493-7. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=7724588 7724588]
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[[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: Ciesla J]]
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[[Category: Ciesla, J.]]
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[[Category: Maley F]]
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[[Category: Maley, F.]]
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[[Category: Montfort WR]]
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[[Category: Montfort, W.R.]]
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[[Category: Weichsel A]]
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[[Category: Weichsel, A.]]
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[[Category: DGP]]
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[[Category: F89]]
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[[Category: methyltransferase]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Wed Nov 21 03:22:32 2007''
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Current revision

THYMIDYLATE SYNTHASE COMPLEXED WITH DGMP AND FOLATE ANALOG 1843U89

PDB ID 1tlc

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