4isk

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{{STRUCTURE_4isk| PDB=4isk | SCENE= }}
 
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===Crystal structure of E.coli thymidylate synthase with dUMP and the BGC 945 inhibitor===
 
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{{ABSTRACT_PUBMED_23710599}}
 
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==Function==
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==Crystal structure of E.coli thymidylate synthase with dUMP and the BGC 945 inhibitor==
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[[http://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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<StructureSection load='4isk' size='340' side='right'caption='[[4isk]], [[Resolution|resolution]] 1.75&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[4isk]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_K-12 Escherichia coli K-12]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ISK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ISK 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]] 1.752&#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=1JY:N-(4-{[(6S)-2-(HYDROXYMETHYL)-4-OXO-4,6,7,8-TETRAHYDRO-1H-CYCLOPENTA[G]QUINAZOLIN-6-YL](PROP-2-YN-1-YL)AMINO}BENZOYL)-L-GAMMA-GLUTAMYL-D-GLUTAMIC+ACID'>1JY</scene>, <scene name='pdbligand=CXM:N-CARBOXYMETHIONINE'>CXM</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=UMC:2-DEOXY-5-URIDYLIC+ACID'>UMC</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=4isk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4isk OCA], [https://pdbe.org/4isk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4isk RCSB], [https://www.ebi.ac.uk/pdbsum/4isk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4isk 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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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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N-[4-[2-Propyn-1-yl[(6S)-4,6,7,8-tetrahydro-2-(hydroxymethyl)-4-oxo-3H-cyclopenta [g]quinazolin-6-yl]amino]benzoyl]-l-gamma-glutamyl-d-glutamic acid 1 (BGC 945, now known as ONX 0801), is a small molecule thymidylate synthase (TS) inhibitor discovered at the Institute of Cancer Research in London. It is licensed by Onyx Pharmaceuticals and is in phase 1 clinical studies. It is a novel antifolate drug resembling TS inhibitors plevitrexed and raltitrexed that combines enzymatic inhibition of thymidylate synthase with alpha-folate receptor-mediated targeting of tumor cells. Thus, it has potential for efficacy with lower toxicity due to selective intracellular accumulation through alpha-folate receptor (alpha-FR) transport. The alpha-FR, a cell-surface receptor glycoprotein, which is overexpressed mainly in ovarian and lung cancer tumors, has an affinity for 1 similar to that for its natural ligand, folic acid. This study describes a novel synthesis of 1, an X-ray crystal structure of its complex with Escherichia coli TS and 2'-deoxyuridine-5'-monophosphate, and a model for a similar complex with human TS.
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==About this Structure==
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Development and Binding Mode Assessment of N-[4-[2-Propyn-1-yl[(6S)-4,6,7,8-tetrahydro-2-(hydroxymethyl)-4-oxo-3H-cyclopenta [g]quinazolin-6-yl]amino]benzoyl]-l-gamma-glutamyl-d-glutamic Acid (BGC 945), a Novel Thymidylate Synthase Inhibitor That Targets Tumor Cells.,Tochowicz A, Dalziel S, Eidam O, O'Connell JD 3rd, Griner S, Finer-Moore JS, Stroud RM J Med Chem. 2013 Jun 21. PMID:23710599<ref>PMID:23710599</ref>
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[[4isk]] is a 8 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ISK OCA].
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==Reference==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<ref group="xtra">PMID:023710599</ref><references group="xtra"/><references/>
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</div>
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[[Category: Thymidylate synthase]]
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<div class="pdbe-citations 4isk" style="background-color:#fffaf0;"></div>
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[[Category: Finer-Moore, J.]]
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[[Category: Stroud, R M.]]
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==See Also==
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[[Category: Tochowicz, A.]]
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*[[Thymidylate synthase 3D structures|Thymidylate synthase 3D structures]]
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[[Category: Alpha/beta protein]]
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== References ==
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[[Category: Dump subtrate]]
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<references/>
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[[Category: Methylase]]
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__TOC__
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[[Category: Methyltransferase]]
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</StructureSection>
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[[Category: Transferase-transferase inhibitor complex]]
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[[Category: Escherichia coli K-12]]
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[[Category: Large Structures]]
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[[Category: Finer-Moore J]]
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[[Category: Stroud RM]]
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[[Category: Tochowicz A]]

Current revision

Crystal structure of E.coli thymidylate synthase with dUMP and the BGC 945 inhibitor

PDB ID 4isk

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