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1ju6

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(New page: 200px<br /> <applet load="1ju6" size="450" color="white" frame="true" align="right" spinBox="true" caption="1ju6, resolution 2.89&Aring;" /> '''Human Thymidylate S...)
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[[Image:1ju6.gif|left|200px]]<br />
 
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<applet load="1ju6" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="1ju6, resolution 2.89&Aring;" />
 
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'''Human Thymidylate Synthase Complex with dUMP and LY231514, A Pyrrolo(2,3-d)pyrimidine-based Antifolate'''<br />
 
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==Overview==
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==Human Thymidylate Synthase Complex with dUMP and LY231514, A Pyrrolo(2,3-d)pyrimidine-based Antifolate==
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Crystal structures of four pyrrolo(2,3-d)pyrimidine-based antifolate, compounds, developed as inhibitors of thymidylate synthase (TS) in a, strategy to circumvent drug-resistance, have been determined in complexes, with their in vivo target, human thymidylate synthase, and with the, structurally best-characterized Escherichia coli enzyme, to resolutions of, 2.2-3.0 A. The 2.9 A crystal structure of a complex of human TS with one, of the inhibitors, the multi-targeted antifolate LY231514, demonstrates, that this compound induces a "closed" enzyme conformation and leads to, formation of a covalent bond between enzyme and substrate. This structure, is one of the first liganded human TS structures, and its solution was, aided by mutation to facilitate crystallization. Structures of three other, pyrrolo(2,3-d)pyrimidine-based antifolates in complex with Escherichia, coli TS confirm the orientation of this class of inhibitors in the active, site. Specific interactions between the polyglutamyl moiety and a, positively charged groove on the enzyme surface explain the marked, increase in affinity of the pyrrolo(2,3-d)pyrimidine inhibitors once they, are polyglutamylated, as mediated in vivo by the cellular enzyme folyl, polyglutamate synthetase.
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<StructureSection load='1ju6' size='340' side='right'caption='[[1ju6]], [[Resolution|resolution]] 2.89&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1ju6]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1JU6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1JU6 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]] 2.89&#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=LYA:2-{4-[2-(2-AMINO-4-OXO-4,7-DIHYDRO-3H-PYRROLO[2,3-D]PYRIMIDIN-5-YL)-ETHYL]-BENZOYLAMINO}-PENTANEDIOIC+ACID'>LYA</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=UMP:2-DEOXYURIDINE+5-MONOPHOSPHATE'>UMP</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=1ju6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1ju6 OCA], [https://pdbe.org/1ju6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1ju6 RCSB], [https://www.ebi.ac.uk/pdbsum/1ju6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1ju6 ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/TYSY_HUMAN TYSY_HUMAN] Contributes to the de novo mitochondrial thymidylate biosynthesis pathway.<ref>PMID:21876188</ref>
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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/ju/1ju6_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=1ju6 ConSurf].
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<div style="clear:both"></div>
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==Disease==
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==See Also==
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Known disease associated with this structure: Timothy syndrome OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=114205 114205]]
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*[[Thymidylate synthase 3D structures|Thymidylate synthase 3D structures]]
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== References ==
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==About this Structure==
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<references/>
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1JU6 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with PO4, UMP and LYA 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=1JU6 OCA].
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__TOC__
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</StructureSection>
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==Reference==
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Multi-targeted antifolates aimed at avoiding drug resistance form covalent closed inhibitory complexes with human and Escherichia coli thymidylate synthases., Sayre PH, Finer-Moore JS, Fritz TA, Biermann D, Gates SB, MacKellar WC, Patel VF, Stroud RM, J Mol Biol. 2001 Nov 2;313(4):813-29. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=11697906 11697906]
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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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: Biermann D]]
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[[Category: Biermann, D.]]
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[[Category: Finer-Moore JS]]
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[[Category: Finer-Moore, J.S.]]
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[[Category: Fritz TA]]
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[[Category: Fritz, T.A.]]
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[[Category: Gates SB]]
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[[Category: Gates, S.B.]]
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[[Category: MacKellar WC]]
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[[Category: MacKellar, W.C.]]
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[[Category: Patel VF]]
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[[Category: Patel, V.F.]]
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[[Category: Sayre PH]]
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[[Category: Sayre, P.H.]]
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[[Category: Stroud RM]]
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[[Category: Stroud, R.M.]]
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[[Category: LYA]]
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[[Category: PO4]]
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[[Category: UMP]]
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[[Category: antifolate]]
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[[Category: cancer]]
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[[Category: drug resistance]]
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[[Category: dtmp synthesis]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 17:44:28 2007''
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Current revision

Human Thymidylate Synthase Complex with dUMP and LY231514, A Pyrrolo(2,3-d)pyrimidine-based Antifolate

PDB ID 1ju6

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