4l5b

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{{STRUCTURE_4l5b| PDB=4l5b | SCENE= }}
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==Human dCK C4S-S74E mutant in complex with UDP and the DI-43 inhibitor==
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===Human dCK C4S-S74E mutant in complex with UDP and the DI-43 inhibitor===
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<StructureSection load='4l5b' size='340' side='right' caption='[[4l5b]], [[Resolution|resolution]] 1.94&Aring;' scene=''>
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{{ABSTRACT_PUBMED_23947754}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[4l5b]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4L5B OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4L5B FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1UX:1-[5-(4-{[(4,6-DIAMINOPYRIMIDIN-2-YL)SULFANYL]METHYL}-5-PROPYL-1,3-THIAZOL-2-YL)-2-METHOXYPHENOXY]-2-METHYLPROPAN-2-OL'>1UX</scene>, <scene name='pdbligand=UDP:URIDINE-5-DIPHOSPHATE'>UDP</scene></td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4jlk|4jlk]]</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DCK ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Deoxycytidine_kinase Deoxycytidine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.74 2.7.1.74] </span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4l5b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4l5b OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4l5b RCSB], [http://www.ebi.ac.uk/pdbsum/4l5b PDBsum]</span></td></tr>
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</table>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Combined inhibition of ribonucleotide reductase and deoxycytidine kinase (dCK) in multiple cancer cell lines depletes deoxycytidine triphosphate pools leading to DNA replication stress, cell cycle arrest, and apoptosis. Evidence implicating dCK in cancer cell proliferation and survival stimulated our interest in developing small molecule dCK inhibitors. Following a high throughput screen of a diverse chemical library, a structure-activity relationship study was carried out. Positron Emission Tomography (PET) using (18)F-L-1-(2'-deoxy-2'-FluoroArabinofuranosyl) Cytosine ((18)F-L-FAC), a dCK-specific substrate, was used to rapidly rank lead compounds based on their ability to inhibit dCK activity in vivo. Evaluation of a subset of the most potent compounds in cell culture (IC50 = approximately 1-12 nM) using the (18)F-L-FAC PET pharmacodynamic assay identified compounds demonstrating superior in vivo efficacy.
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==Function==
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Development of new deoxycytidine kinase inhibitors and noninvasive in vivo evaluation using positron emission tomography.,Murphy JM, Armijo AL, Nomme J, Lee CH, Smith QA, Li Z, Campbell DO, Liao HI, Nathanson DA, Austin WR, Lee JT, Darvish R, Wei L, Wang J, Su Y, Damoiseaux R, Sadeghi S, Phelps ME, Herschman HR, Czernin J, Alexandrova AN, Jung ME, Lavie A, Radu CG J Med Chem. 2013 Sep 12;56(17):6696-708. doi: 10.1021/jm400457y. Epub 2013 Aug, 15. PMID:23947754<ref>PMID:23947754</ref>
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[[http://www.uniprot.org/uniprot/DCK_HUMAN DCK_HUMAN]] Required for the phosphorylation of the deoxyribonucleosides deoxycytidine (dC), deoxyguanosine (dG) and deoxyadenosine (dA). Has broad substrate specificity, and does not display selectivity based on the chirality of the substrate. It is also an essential enzyme for the phosphorylation of numerous nucleoside analogs widely employed as antiviral and chemotherapeutic agents.<ref>PMID:18377927</ref> <ref>PMID:20614893</ref>
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[4l5b]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4L5B OCA].
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</div>
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==Reference==
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==See Also==
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<ref group="xtra">PMID:023947754</ref><references group="xtra"/><references/>
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*[[Deoxycytidine kinase|Deoxycytidine kinase]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Deoxycytidine kinase]]
[[Category: Deoxycytidine kinase]]
[[Category: Human]]
[[Category: Human]]
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[[Category: Lavie, A.]]
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[[Category: Lavie, A]]
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[[Category: Nomme, J.]]
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[[Category: Nomme, J]]
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[[Category: Deoxycytidine kinase]]
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[[Category: Phosphoryl transfer]]
[[Category: Phosphoryl transfer]]
[[Category: Phosphorylation]]
[[Category: Phosphorylation]]
[[Category: Transferase-transferase inhibitor complex]]
[[Category: Transferase-transferase inhibitor complex]]

Revision as of 18:48, 21 December 2014

Human dCK C4S-S74E mutant in complex with UDP and the DI-43 inhibitor

4l5b, resolution 1.94Å

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