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1tls

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[[Image:1tls.gif|left|200px]]<br />
 
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<applet load="1tls" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="1tls, resolution 2.6&Aring;" />
 
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'''THYMIDYLATE SYNTHASE TERNARY COMPLEX WITH FDUMP AND METHYLENETETRAHYDROFOLATE'''<br />
 
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==Overview==
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==THYMIDYLATE SYNTHASE TERNARY COMPLEX WITH FDUMP AND METHYLENETETRAHYDROFOLATE==
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Two crystal structures for E. coli thymidylate synthase (TS) bound to the, mechanism-based inhibitor 5-fluoro-dUMP (FdUMP) and, methylenetetrahydrofolate (CH2THF) have been determined to 2.6 and 2.2 A, nominal resolutions, with crystallographic R factors of 0.180 and 0.178, respectively. The inhibitor and cofactor are well ordered in both, structures and display covalent links to each other and to Cys 146 in the, TS active site. The structures are in general agreement with a previous, report for this complex (D. A. Matthews et al. (1990) J. Mol. Biol. 214, 937-948), but differ in two key respects: (i) the methylene bridge linking, FdUMP and CH2THF is rotated about 60 degrees to a different position and, (ii) the electron density for C6 of FdUMP, which is covalently linked to, Cys 146, is more diffuse than for the other atoms in the pyrimidine ring., The ligand arrangement observed in the previous structure led the authors, to propose that a large conformational change in ligand geometry must, occur in order to facilitate catalysis and yield the correct chirality in, the methyl of product dTMP. The new structures suggest a different, mechanism for product formation that does not require ligands to greatly, alter their conformations during catalysis and which makes use of, instability in the nucleotide-Cys 146 thiol adduct to avoid a deep free, energy well and assist in proton abstraction from dUMP. All intermediates, in the proposed mechanism were modeled and energy minimized in the TS, active site, and all can be accommodated in the present structures. The, role of ligand-induced conformational change in the TS mechanism and the, possibility of Tyr 94 acting as a base during catalysis are also, discussed.
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<StructureSection load='1tls' size='340' side='right'caption='[[1tls]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1tls]] 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=1TLS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1TLS 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]] 2.6&#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=C2F:5-METHYL-5,6,7,8-TETRAHYDROFOLIC+ACID'>C2F</scene>, <scene name='pdbligand=CXM:N-CARBOXYMETHIONINE'>CXM</scene>, <scene name='pdbligand=UFP:5-FLUORO-2-DEOXYURIDINE-5-MONOPHOSPHATE'>UFP</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=1tls FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1tls OCA], [https://pdbe.org/1tls PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1tls RCSB], [https://www.ebi.ac.uk/pdbsum/1tls PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1tls 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/1tls_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=1tls 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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1TLS 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 UFP and C2F 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 Sites: S1 and S2. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1TLS 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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Use of strain in a stereospecific catalytic mechanism: crystal structures of Escherichia coli thymidylate synthase bound to FdUMP and methylenetetrahydrofolate., Hyatt DC, Maley F, Montfort WR, Biochemistry. 1997 Apr 15;36(15):4585-94. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=9109668 9109668]
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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: Hyatt DC]]
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[[Category: Hyatt, D.C.]]
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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: C2F]]
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[[Category: UFP]]
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[[Category: methyltransferase]]
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[[Category: transferase]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 5 17:05:46 2007''
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Current revision

THYMIDYLATE SYNTHASE TERNARY COMPLEX WITH FDUMP AND METHYLENETETRAHYDROFOLATE

PDB ID 1tls

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