View source for 8fvc


==E coli. CTP synthase in complex with dF-dCTP (potassium malonate + 5 mM MgCl2)==
<StructureSection load='8fvc' size='340' side='right'caption='[[8fvc]], [[Resolution|resolution]] 2.28&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8fvc]] 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=8FVC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8FVC FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.281&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GTF:2-DEOXY-2,2-DIFLUOROCYTIDINE+5-(TETRAHYDROGEN+TRIPHOSPHATE)'>GTF</scene>, <scene name='pdbligand=MLA:MALONIC+ACID'>MLA</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8fvc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8fvc OCA], [https://pdbe.org/8fvc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8fvc RCSB], [https://www.ebi.ac.uk/pdbsum/8fvc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8fvc ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/PYRG_ECO45 PYRG_ECO45] Catalyzes the ATP-dependent amination of UTP to CTP with either L-glutamine or ammonia as the source of nitrogen. Regulates intracellular CTP levels through interactions with the four ribonucleotide triphosphates.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
CTP synthases (CTPS) catalyze the de novo production of CTP using UTP, ATP, and l-glutamine with the anticancer drug metabolite gemcitabine-5'-triphosphate (dF-dCTP) being one of its most potent nucleotide inhibitors. To delineate the structural origins of this inhibition, we solved the structures of Escherichia coli CTPS (ecCTPS) in complex with CTP (2.0 A), 2'-ribo-F-dCTP (2.0 A), 2'-arabino-F-CTP (2.4 A), dF-dCTP (2.3 A), dF-dCTP and ADP (2.1 A), and dF-dCTP and ATP (2.1 A). These structures revealed that the increased binding affinities observed for inhibitors bearing the 2'-F-arabino group (dF-dCTP and F-araCTP), relative to CTP and F-dCTP, arise from interactions between the inhibitor's fluorine atom exploiting a conserved hydrophobic pocket formed by F227 and an interdigitating loop from an adjacent subunit (Q114-V115-I116). Intriguingly, crystal structures of ecCTPS*dF-dCTP complexes in the presence of select monovalent and divalent cations demonstrated that the in crystallo tetrameric assembly of wild-type ecCTPS was induced into a conformation similar to inhibitory ecCTPS filaments solely through the binding of Na(+) -, Mg(2+) -, or Mn(2+) *dF-dCTP. However, in the presence of potassium, the dF-dCTP-bound structure is demetalated and in the low-affinity, non-filamentous conformation, like the conformation seen when bound to CTP and the other nucleotide analogues. Additionally, CTP can also induce the filament-competent conformation linked to high-affinity dF-dCTP binding in the presence of high concentrations of Mg(2+) . This metal-dependent, compacted CTP pocket conformation therefore furnishes the binding environment responsible for the tight binding of dF-dCTP and provides insights for further inhibitor design.

A metal-dependent conformational change provides a structural basis for the inhibition of CTP synthase by gemcitabine-5'-triphosphate.,McLeod MJ, Tran N, McCluskey GD, Gillis TD, Bearne SL, Holyoak T Protein Sci. 2023 Jun;32(6):e4648. doi: 10.1002/pro.4648. PMID:37106216<ref>PMID:37106216</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8fvc" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Escherichia coli]]
[[Category: Large Structures]]
[[Category: Holyoak T]]
[[Category: McLeod MJ]]
[[Category: Tran N]]